polymorphisms in the human cytochrome p450 and arylamine n-acetyltransferase: susceptibility to head...

Hindawi Publishing CorporationBioMed Research InternationalVolume 2013 Article ID 582768 20 pageshttpdxdoiorg1011552013582768

Review ArticlePolymorphisms in the Human Cytochrome P450 and ArylamineN-Acetyltransferase Susceptibility to Head and Neck Cancers

Rim Khlifi12 Olfa Messaoud3 Ahmed Rebai2 and Amel Hamza-Chaffai1

1 Research Unit on Toxicology and Environment Sfax University 3018 Sfax Tunisia2 Bioinformatics Unit Centre of Biotechnology of Sfax Sfax University 3018 Sfax Tunisia3 Biomedical Genomics and Oncogenetics Laboratory LR11IPT05 University of Tunis El Manar 1002 Tunis Tunisia

Correspondence should be addressed to Rim Khlifi rimkhlifiyahoofr

Received 19 April 2013 Revised 25 June 2013 Accepted 24 July 2013

Academic Editor Li Jiao

Copyright copy 2013 Rim Khlifi et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

The occurrence of head and neck cancer (HNC) is associated with smoking and alcohol drinking Tobacco smoking exposessmokers to a series of carcinogenic chemicals Cytochrome P450 enzymes (CYP450s) such as CYP1A1 CYP1B1 and CYP2D6usuallymetabolize carcinogens to their inactive derivatives but they occasionally convert the chemicals tomore potent carcinogensIn addition via CYP450 (CYP2E1) oxidase alcohol is metabolized to acetaldehyde a highly toxic compound which plays animportant role in carcinogenesis Furthermore two N-acetyltransferase isozymes (NATs) NAT1 and NAT2 are polymorphicand catalyze both N-acetylation and O-acetylation of aromatic and heterocyclic amine carcinogens Genetic polymorphisms areassociated with a number of enzymes involved in the metabolism of carcinogens important in the induction of HNC It has beensuggested that such polymorphisms may be linked to cancer susceptibility In this paper we select four cytochrome P450 enzymes(CYP1A1 CYP1BA1 CYP2D6 and CYP2E1) and two N-acetyltransferase isozymes (NAT1 and NAT2) in order to summarize andanalyze findings from the literature related toHNC risk by focusing on (i) the interaction between these genes and the environment(ii) the impact of genetic defect on protein activity andor expression and (iii) the eventual involvement of race in such associations

1 Introduction

Head and neck squamous cell carcinoma (HNSCC) is thefifth most common cancer worldwide and is associated withlow survival and highmorbidity when diagnosed in advancedstage [1 2] This type of cancer accounts for almost 500000newly diagnosed cancer cases per year [3 4] Epidemio-logical studies have shown that HNSCC occurs through acomplex multistage process that may involve exposure to acombination of carcinogens from cigarette smoking [5 6]alcohol consumption [7] or tobacco chewing [8 9] As insome regions of the world these toxic agents are responsiblefor about 75 of all cancer cases HNSCC is used to beconsidered as a tobacco-induced and a preventable cancer[4 10] The hypothesis that genetic susceptibility or predis-position is of important role in head and neck cancer (HNC)etiology is highly supported by case-control studies of severalphenotypic and genotypic assays [11ndash13] Some studies statedthat gene-environment interactions in relation to HNSCC

are linked to genes involved in metabolism enzymes foralcohol and tobacco smoke constituents [14] Polymorphismsin the genes encoding these enzymes by altering theirexpression and functionmay increase or decrease carcinogenactivationdetoxification followed by modulation of cancerrisk [15 16]

Polymorphisms in the carcinogen-metabolizing geneshave been analyzed on individual basis [17] Several studieshave addressed the relationship between the genetic poly-morphisms of enzymes involved in the metabolic activationof carcinogens and the occurrence of HNSCC [15 18 19]Genetic polymorphisms in cytochrome P450 (ie CYP1A1CYP1B1 CYP2D6 and CYP2E1) and N-acetyltransferase(NAT1 andNAT2) enzymes involved in the biotransformationof the carcinogenic constituents of tobacco have been shownto be the risk factors involved in HNSCC [20ndash23] Theseenzymes are very important with respect to the metabolismof a large number of xenobiotic carcinogens (Table 1)Carcinogens present in tobacco smoke such as polycyclic

2 BioMed Research International

Table1Po

lymorph

icCY

PsP4

50andNAT

sand

metabolism

ofcarcinogensintheH

NC

Gene

Substrate

Reference

Functio

naleffect

Polymorph

ismrsnu

mber

Reference

CYP1A1

TCa(egbenzo[a]pyrene

dimethylbenz[a]anthracene)

6-nitro

chrysene

[33]

PhaseI

oxidativea

ndredu

ctive

CYP1A1lowast

2A(m

1)Trarr

Csubstitutionatnu

cleotide

6235

inthe31015840

noncod

ingregion

mdash

[35]

CYP1A1lowast

2B(m

2)Ararr

GIle

462V

alrs1048943

CYP1A1lowast

3(m

3)Trarr

Csubstitutionatnu

cleotide

5996

inthe31015840

noncod

ingregion

mdash

CYP1A1lowast

4(m

4)Crarr

ATh

r461As

nrs1799814

CYP1B1

TCa(egbenzo[a]pyrene)

[92]

PhaseI

oxidativea

ndredu

ctive

CYP1B1lowast

3Va

l432Leu

rs1056836

[101]

CYP1B1lowast

2Arg48Ser

rs1056827

CYP1B1lowast

2Ala119

Ser

rs10012

CYP1B1lowast

4As

n453Ser

rs1800

440

CYP2

D6

TCa(egnicotin

eand

nitro

samines)

[126]

PhaseI

oxidativea

ndredu

ctive

CYP2

D6lowast3(single-base

deletio

natexon

52549delA)

rs35742686

[129]

CYP2

D6lowast4(G

1934A)

rs3892097

CYP2

D6lowast5(le

adingto

gene

deletio

n)mdash

CYP2


deletio

natexon

31707delT)

rs5030655

CYP2

E1TC

a(egnitro

samines)

Ethano

l[24143144]

PhaseI

oxidativea

ndredu

ctive

CYP2

E1lowast

5B(c2)

(PstI

restric

tion

positionminus1019)

mdash[14

2]CY

P2E1lowast

5A(c1)(RsaIrestrictio

npo

sitionminus1259)

mdashCY

P2E1lowast

6(alleleD)(DraIrestrictio

nintro

n6)

rs64

13432

[149]

NAT1NAT

2Arylamines

andheterocyclica

romatic

amines

[181184186187]Ph

aseIIb

iotransfo

rmation

NAT1lowast

10T

1088A

rs1057126

[188]

NAT1lowast

10C

1095A

rs15561

NAT2lowast

5BIle114

Thr

NAT2lowast

5BLys268A

rgrs1801280

rs1208

NAT2lowast

6AA

rg197G

lnrs1799930

a Tob

acco

carcinogensmdashund

efined

BioMed Research International 3

hydrocarbons including the prototype of this chemical classbenzo(a)pyrene [24 25] and tobacco-specific nitrosamines(TSNAs) have been implicated in HNC etiology in smokers[26] It was previously suggested that acetaldehyde the firstmetabolite of alcohol when orally ingested is involved inalcohol-related cancer induction Nevertheless carcinogenicpathway of alcohol is not elucidated [27]

In the present paper we summarize results of studies(published up to February 2013) dealing with the associationbetween the genetic variations in genes coding for phases Iand II carcinogen metabolism enzymes (CYP1A1 CYP1BA1CYP2D6 CYP2E1 NAT1 and NAT2) and the increased riskof head and neck cancer development

2 Cytochrome P450 (CYP450)

The determinant factors for HNSCC development remainunclear Although the importance of tobacco and alcoholconsumption as risk factors suggests that genes encodingdetoxifying enzymes are susceptibility candidates severaldata have not confirmed associations between these enzymesand the occurrence of HNSCC Previous studies suggest thatvarious CYP genotypes are linked with its outcome ratherthan its susceptibility [28 29]

21 CYP1A1 The human enzyme CYP1A1 is the most activeamong the CYPs in metabolizing procarcinogens partic-ularly the polycyclic aromatic hydrocarbons (PAHs) intohighly reactive intermediates [30] When these compoundsbind to DNA and form adducts they may contribute tocarcinogenesis Despite the fact that PAHs are ubiquitousin the environment remarkable sources of exposure suchas smoking certain occupations and air pollution maylead to the greatest concern [31] The aromatic hydrocarbonreceptor is a key activator of the CYP1A1 gene [32 33] PAHswere classified among important toxicants as they induceCYP1A1 gene and act as precarcinogenic substrates [34 35]The relationship between CYP1A1 variants and cancer riskhas been investigated in several studies [18] CYP1 enzymesare coupled to phase II detoxification in vivo It has beenproposed that compared with other CYP1 enzymes CYP1A1is more tightly coupled to phase II metabolism and playsa more important role in vivo in detoxification than toxinactivation [36]

A recent study confirmed the importance of tobaccosmoking as the main risk factor for the upper aerodigestivetract (UADT) indicating that about 68 of cancers can beattributed to this risk factor A significant association betweenmetabolizing phase I genes (CYP1A1) and UADT cancers wasfound [37] Nagaraj et al [38] identified molecular factorswhich contribute to the increased risk of smokers for oralsquamous cell carcinoma (OSCC) In fact they evaluategene expression profile change according to cigarette smokecondensate in normal epidermal keratinocytes oral dysplasiacell lines Leuk1 and Leuk2 and a primary oral carcinomacell line 101A Their results have shown that treatment bycigarette smoke condensate acts on several cell types andusually leads to overexpression of CYP1A1 These findings

support the hypothesis that cigarette smoke condensate iswidely involved in the activation of procarcinogens Theseresults are similar to those of Chi et al [39] and those of Wenand Walle [40]

A functional role has been previously assigned to twononsynonymous polymorphisms in the CYP1A1 gene Thefirst one is an adenine (A) to guanine (G) substitution atcodon 462 in exon 7 (Ile462Val rs1048943) The second oneis a thymine (T) to cytosine (C) transition (rs4646903) [41]This last mutation changes a restriction site for the MspIenzyme thus resulting in three genotypes a predominanthomozygous allele (genotype A TT) a heterozygous allele(genotype B TC) and a homozygous rare allele (genotype CCC) [42] Contrary to genotype C genotype A abolishes therestriction enzyme site of MspI The exon 7 restriction-sitepolymorphism resulted in three genotypes the predominanthomozygous (IleIle) the heterozygous (IleVal) and the rarehomozygous (ValVal) Another mutation CYP1A1 T6235C(m1) located in the 31015840 end of this gene is considered asa polymorphism for the restriction endonuclease MspI andresults in a mutant CYP1A1 allele designated as CYP1A1lowast2AThree additional polymorphisms have also been reported inexon 7 of the CYP1A1 geneThe first one is a CYP1A1 4889AG(m2) transversion responsible for the replacement of Ile byVal at position 462 in the mutant form of the protein and it isknown as CYP1A1lowast2B The second polymorphism is causedby a CYP1A1 T5996C (m3) transition in the 31015840 noncodingregion of the gene which is known as CYP1A1lowast3 The last oneis located at position 4887 and is a transversion a CYP1A14887CA (m4) that results in a mutation of Thr to Asnat codon 461 (CYP1A1lowast4) [41 43 44] Among these fourpolymorphisms the MspI at the 31015840 flanking region has beenreported in many epidemiological studies to be associatedwith cigarette smoking-related cancer risk in some but notall studies [18 41 43 45ndash52]

Several studies have been since performed examiningthe potential association between the polymorphic CYP1A1(MspI andor exon 7) and the HNC occurrence (Figure 1)In the Brazilian patients a tendency of increased oral cancerrisk among CYP1A1 genotypes (426ValVal) that comparedboth with the wild-type homozygous (OR = 285) andheterozygous (OR = 261) ones was found by Marqueset al [53] The CYP1A1 (426ValVal) genotype was foundthree times more frequent than in controls in 3 of oralcancer patients In spite of the absence of any statisticalsignificance these results strongly supported the previousones showing that the mutant allele CYP1A1 426Val is relatedto an increased risk of oral cancer in Caucasians in theUnited States [47] among Asian populations [54] and inIndians [19] It was also reported that the CYP1A1 4889AGgenotype [Ile462Val (rs1048943)] is more frequent in thegroup of white HNSCC patients (10 119899 = 108) than inwhite controls (7 119899 = 165) [15] However for genotypeheterozygous the moderate increase in the HNSCC risk wasnot statistically significant Nevertheless it was reported anoverrepresentation of the CYP1A1 4889G allele among thenonsmoking Caucasian patients with oral cancer [47] andamong the Japanese HNSCC patients [55] For the Polishpatients the increased frequency of the CYP1A1lowast4 allele and


1 2 43 5 6 87 109 11 120

5

10

15

20

25

30

Odd

s rat

io

lowast2

Alowast2

A

lowast2

Alowast2

A

lowast2

Alowast2

A

lowast1

Alowast2

A

lowast2

Alowast2

Am2

m2

m2

m2

m2

m2

Msp

Ia

Msp

I T3801

C

lowast2

Clowast2

C3798

CC3798

CTm1

m1

w1

m1

lowast4

lowast4

Figure 1 Odds ratios (OR) for HNC obtained from 12 CYP1A1studies Bars indicate 95 confidence intervals (CI) while individ-ual SNPs in each study are labeled for each vertical line and studynumbers are indicated at the bottom (1 [69] 2 [66] 3 [64] 4 [63]5 [62] 6 [65] 7 [68] 8 [89] 9 [55] 10 [60] 11 [79] 12 [56])aSmokers

the CYP1A1lowast4lowast4 genotype (CYP1A1Thr461Asn) supports itsassociation with HNC and might be specific for laryngealSCC [56] However Reszka et al [57] and Amtha et al[58] suggested no significant increase in HNC risk in thePolish and Indonesian patients respectively with theCYP1A1462Val alleles (OR = 160 and 070 resp) Moreover in arecent meta-analysis study no association between Ile462Valpolymorphism and HNC risk was found [59]

Polymorphisms located in the CYP gene result in theenzyme activity increase [60] The homozygous CYP1A1(MspI) mutations are present in 7 to 10 of the whitepopulation and in up to 33 of the Japanese populationThese homozygous (m2m2) polymorphisms were associatedwith a high susceptibility to SCC of the lung or UADTaccording to some researches [61 62] To investigate theassociation between CYP1A1 polymorphism (MspI) and riskforOSCC in the Korean [63] and the Indian [64] populationsmany studies have been conducted and they found that therisk for oral cancer was significantly increased in subjectsof these populations with the homozygous CYP1A1 (m2m2)genotype (Indian OR = 32 95 CI = 110ndash1028 and119875 = 005 Korean OR = 38 95 CI = 19ndash77 and 119875 =0023) regardless of smoking history (smokers OR = 44and 95 CI = 12ndash163 nonsmokers OR = 49 and 95CI = 19ndash125) Recently in Liu et al [59] meta-analysisa significant association between MspI SNP and HNC riskwas found (95 CI = 115ndash157 119875 lt 0001) This effectwas found to be more pronounced in smokers (OR = 29895 CI = 169ndash526 and 119875 lt 0001) thus demonstratingthat gene-smoking interaction that intensifies carcinogenesismight exist [59] Additionally Sam et al [65] found thatthe individuals polymorphic for CYP1A1 MspI revealed anincreased risk for UADT cancers than that ascribed to asingle susceptible gene among tobacco users in the Indianpopulation (OR = 643 95 CI = 369ndash1121) Moreover ina previous study Sam et al [66] found that CYP1A1lowast1Alowast2Aand lowast2Alowast2A polymorphic genotypes are associated withan enhanced risk to UADT cancers in particular amongthe habitual tobacco smokers and chewers carrying mutantgenotypes in the Indian population (OR = 176 95 CI =

119ndash260 and OR = 283 95 CI = 143ndash561 resp)Furthermore Olivieri et al [67] Figaro Gatta et al [68]Tanimoto et al [69] and Singh et al [23] reported thatthe Brazilian the Japanese and the North Indian patientscarryingCYP1A1 (lowast1Alowast2A) genotype presented an increasedHNSCC risk However no statistically significant differencein theCYP1A1lowast2A allele and in theCYP1A1lowast2Alowast2Agenotypefrequency was found in Gajecka et al study [56]

Many researches focused on the association of CYP1A1polymorphismwith susceptibility to laryngeal cancer Unfor-tunately their results were inconsistent and inconclusiveCYP1A1MspI polymorphismwas found to be a risk factor forlaryngeal cancer in Caucasians (OR = 129) but not in Asians(OR = 138) [70] Variant genotypes of CYP1A1 might notbe considered as risk factors for oral cancer [70] MoreoverTai et al [71] studied CYP1A1 polymorphisms in the Chinesepatients with laryngeal and hypopharyngeal SCC and controlsubjects They found an increased risk associated with theCYP1A1 3798CC genotype (OR = 239 95 CI = 111ndash516)compared with the TT genotype [71] In other investigationsno such association was found [72ndash74] In the Gronau et alreport [75] a German case-control study the authors foundthat the homozygous mutation and the MspI restriction sitein exon 7 are present only once in the control group andthat no patient revealed this genotype Furthermore thegenotype frequencies at the CYP1A1 gene loci investigatedin other German case-control studies showed no differencesbetween these groups suggesting a lack of influence of thesegenes in the susceptibility to laryngeal cancer [28 76] Theassociation of nasopharyngeal cancer (NPC) in Taiwan withCYP1A1 MspI genetic polymorphism was studied [77] andno significant associations of the examined genotypes withNPC risk were noted Moreover a recent study [78] of twoSNPs in CYP1A1 m1 [MspI (rs4646903)] and CYP1A1 m2[Ile462Val (rs1048943)] in a total of 457 Cantonese nuclearfamilies consisting of 2134 members has concluded thatthere is no absence of any statistical significance between m1polymorphism and susceptibility to NPC However m2 poly-morphism might be associated with NPC in the Cantonesenuclear families (119875 = 0045) [78]

It is noteworthy that all studies on the relationshipbetween CYP1A1 genotype and cancer have focused on eachpolymorphism separately Having global information regard-ing the individual haplotype could give better clarification ofsuch associations Recently Sabitha et al [79] examined forthe first time the association of three SNPs in the CYP1A1MspI locus (m1m1 w1w1 andm2m2) with HNC riskTheyfound that individuals carrying at least one CYP1A1 m1or m2 variant allele were at a 2-fold elevated risk for HNCand concluded that CYP1A1 is an important determinant insusceptibility to tobacco-induced HNC among Indians [79]Cigarette smoke has been shown to upregulateCYP1A1 underin vitro conditions as well as in smokers [38 39 80] Infive earlier different studies investigating CYP1A1 genotype-smoking interactions [48 81ndash84] two have reported evidenceof an interaction [81 84] Further few studies [28 72 85 86]did not find a relationship between pack-years of smokingand risk of HNSCC among cases with theCYP1A1MspI poly-morphism But recently Sabitha et al [79] found association


between pack-years of smoking and risk of HNSCC amongcases with the CYP1A1 MspI polymorphism Heavy smokersshowed an increased risk for HNC in association with bothm1 and m2 mutations The OR of HNC for the variantCYP1A1m1 genotype the tobacco smoking and both factorscombined were OR = 493 95 CI = 183ndash1368 107 95CI = 016ndash734 060 95 CI = 030ndash118 respectivelySabitha et al [79] findings support that CYP1A1 m1 andCYP1A1m2 polymorphisms were associated with smoking-related HNC in India

Association of more than one SNP in one individual mayadditively or synergistically contribute to the increased can-cer risk Furthermore the impact of xenobiotic-metabolizingenzymes and transporters could determine the functionalresults in the risk of HNC over the independent effects ofeach single susceptibility gene It is becoming clearly evidentthat single gene or single environmental factor cannot explainsusceptibility to diseases with complex etiology such asHNCExpression of these enzymes might be one of the reasons forinterindividual differences in HNC risks In a recent studyMasood et al [87] studied the expression of CYP1A1 MspI inHNC tumor and normal healthy tissues and the relationshipwith stages of HNC in the Pakistani population They foundthat the CYP1A1 mRNA is less expressed in head and neckcarcinoma compared with adjacent normal tissue (OR = 4595 CI = 15ndash134) CYP1A1 expression was downregulatedaccording to tissue stage as follows 625 in tissues of stage 1727 in tissues of stage 2 60 in tissues of stage 3 and 100in tissues of stage 4 Therefore it is very obvious to concludethat CYP expression is involved in the carcinogenesis by apathway that is still not elucidated

Recently Sharma et al [88] explored the North Indianpopulation by a multifactor dimensionality reductionmethod in order to determine potential gene-environmentand gene-gene interactions that predispose to HNC Theyobserved significant gene-gene interactions among GSTM1copy number variants and CYP1A1 T3801C (rs4646903)variant among smokers This method showed that thecombining three factors smoking status CYP1A1 T3801Cand GSTM1 copy number variants conferred morethan 4-fold increased risk of HNC (OR = 489 95CI = 315ndash732 119875 lt 001) Therefore genetic variants intobacco-metabolizing genes may contribute to HNC riskthrough gene-gene and gene-environment interactionsIn a previous study of Sharma et al [89] research groupepigenetic modifications of genes involved in carcinogenmetabolism pathway CYP1A1 CYP2A13 and GSTM1 wereassessed by evaluating the role of aberrant hypermethylationas well as its relation to tobacco and alcohol consumptionIn addition CYP1A1 and CYP2A13 polymorphisms werealso investigated in the Indian population Results of thisstudy showed that hypermethylation of CYP1A1 and GSTM1showed significant association with HNC (119875 = 0027 and119875 = 0010 resp) They also showed a significant interactionbetween smoking and methylation status of CYP1A1 andCYP2A13 in HNC (119875 = 0029 and 119875 = minus0034 resp) Sohypermethylation of carcinogen metabolism pathway genesis associated with an increased risk of HNC regardless of thesmoking status [89]

In a recent case-control Indian population study [90]the CYP1A1 (lowast2A and lowast2C) CYP2E1 (lowast1B lowast5B and lowast6)and GST (M1 T1 and P1) adenosine triphosphate-bindingcassette B1 3435CgtT (ABCB1) polymorphisms were studiedResults showed a high risk of gene-gene interactions withthe concurrent deletions of GSTT1 and GSTM1 genotypesassociated with variant genotypes of CYP1A1lowast2A (OR =821 95 CI = 191ndash4948) GSTT1 and GSTM1-deficientgenotypes with CYP2E1lowast1B variant genotypes (OR = 67395 CI = 132ndash2281) and a very high risk with thecombined variant genotypes of CYP1A1lowast2A GSTT1 andABCB1 (OR = 1114 95 CI = 270ndash4602) Thus showingthat interaction with many drug-metabolizing enzymes andtransporter proteins is of a high risk for UADT cancerscompared with that of a single susceptible gene [90] Theinteraction between phase II deficient enzymes and a phaseI hyperactive enzyme (CYP1A1) is of interest as it can leadto a larger amount of toxic compounds that may play acrucial role in the initiation or progression of UADT cancersThe risk of cancers is frequently higher in individuals withcombined mutant genotypes of CYP1A1lowast2A and GSTM1null genotype than in those with CYP1A1 or GSTM1 genealone The interaction between CYP1A1 and GSTM1 is soimportant In fact it can be related to CYP1A1 induction [91]The significant risk for oral cancer among carriers of bothCYP1A1lowast2A homozygous variant and GSTM1 null genotypepreviously suggested by Anantharaman et al [64] was alsosupported by Indian Japanese Korean and Brazilian studies[62 63 68 69]

22 CYP1B1 Human CYP1B1 is located on chromosome 2 atthe 2p21-22 region [92 93] The length of its genomic DNAis 12 kilobases (kbs) and the length of its mRNA is asymp52 kbThe CYP1B1 enzyme (cytochrome P450 family 1 subfamilyB and polypeptide 1) is a hemethiolate monooxygenaseinvolved in metabolizing xenobiotics such as polycyclicaromatic hydrocarbons (PAHs) [92] At transcriptional levelCYP1B1 gene is activated by PAHs that constitute the majorconstituents of cigarette smoke and tobacco hence making itresponsive to smoked and smokeless (chewing) tobacco [4092 94] As CYP1B1 is crucially involved in the bioactivationof chemically diverse tobacco-related procarcinogens to reac-tive metabolites its expression is considered as a significantparameter of carcinogenesis [95] Other expression studiesshowed that CYP1B1 is overexpressed in several humantumors in comparison with normal tissues [94 96 97] It wasalso demonstrated the implication of many allelic variationsin CYP1B1 in modulating the incidence of several types ofcancers [98 99] Therefore CYP1B1 played an important rolein carcinogenesis

In humans CYP1B1 locus has been demonstrated to begenetically polymorphic where many mutations have beenidentified in CYP1B1 gene so far [100] Four nonsynony-mous single-nucleotide polymorphisms (SNPs) have beendescribed (i) Arg to Ser at codon 48 (CYP1B1lowast2) (rs10012)(ii) Ala to Ser at codon 119 (CYP1B1lowast2) (iii) Leu to Val atcodon 432 (CYP1B1lowast3) (rs1056836) and (iv) Asn to Ser atcodon 453 (CYP1B1lowast4) (rs1800440) [101] The association


of SNPs in CYP1B1 with the increased risk of ovarianendometrial renal and prostate cancers as well as smoking-related lung cancer has been reported in the Caucasian andthe Japanese populations [102] Contradictorily Aklillu etal [101] have shown that CYP1B1 variant enzymes differ intheir catalytic activity according to the metabolism of 17120573-estradiol It has been reported that proteins presenting oneof the four common SNPs (Arg48Ser Ala119Ser Leu432Valand Asn453Ser) had slight effects on benzo[a]pyrene-78-diol metabolism [103 104] This genotype is then con-sidered as a susceptibility factor to develop PAH-inducedcancers Few epidemiological studies aimed at evaluatinga possible association between genetic polymorphisms ofCYP1B1 and susceptibility to HNSCC have been conducted[105 106]

Two authors have studied the CYP1B1lowast3 polymorphismand identified the susceptibility factor for HNSCC [21 26]In fact genotype and haplotype frequencies of the four SNPsin CYP1B1 have been evaluated in HNSCC patients of theIndian population [21] Singh et al [21] study indicates aseveral-fold increase in cancer risk among cases that usetobacco chewing with the variant genotypes of CYP1B1lowast2(OR = 880 95 CI = 260ndash2987 119875 lt 005) and CYP1B1lowast3(OR = 274 95 CI = 112ndash670 119875 lt 005) suggestingthat interaction between genes and environment plays animportant role in susceptibility to HNSCC Another signif-icant interaction between the variant genotypes of CYP1B1lowast2and cigarette smoking was also found in smoking patients(OR = 237 95 CI = 162ndash485 119875 lt 005) Howeverfor CYP1B1lowast3 and CYP1B1lowast4 genotypes (heterozygous andhomozygous mutants) no significant interaction regardingsmoking with relation to HNSCC has been observed [21]In contrast to Singh et al [21] findings Ko et al [26]reported the presence of variant genotypes of CYP1B1lowast3 at asignificantly higher frequency in smoking patients comparedwith healthy smokers thus suggesting that genotypes ofCYP1B1lowast3 significantly interact with smoking and likelyrepresent a susceptibility factor in smoking related toHNSCC(OR = 453 95 CI = 262ndash798 119875 lt 0001) Li etal [106] failed to find any significant interaction betweentobacco smoking and CYP1B1lowast3 in HNSCC and explainedtheir different results by ethnic backgrounds (Europeansversus American Caucasians) Indeed there are significantdifferences in the allele frequency ofCYP1B1lowast2 andCYP1B1lowast3variants between Caucasians and Asians [107] and Indians[21] The variant allele of CYP1B1lowast2 was more frequent in theIndian controls compared with the Caucasians This couldexplain the higher risk for HNSCC in Singh et al [21] studyHowever there were no significant associations betweenthe risk of hypopharyngeal and laryngeal SCC developmentand CYP1B1 Leu432Val genotypes [71] The difference inthe genetic background related to the ethnic origin of eachpopulation or the involvement of other confounding geneticfactors responsible for HNSCC might explain absence ofassociations

It is well known that the use of tobacco is often accom-panied by alcohol consumption [108] Many studies havereported a high risk of HNC in alcohol drinkers (adjusted forsmoking) Depending on the consumed alcohol amount this

risk varies from less than 2 to 12 folds [9 109] Despite the factthat interaction between alcohol and CYP1B1 genotypes inpromoting HNSCC risk is still unknown it is suggested thattobacco carcinogens are dissolved in alcohol thus facilitatingtheir access to the mucosa of upper aero-digestive organs[110] A strong interaction between alcohol consumption andthe CYP1B1lowast2 genotypes for the increased risk to HNSCCwas also established [21] This interaction was associated inpatients with a heterozygous genotype of CYP1B1lowast2 (OR =607 119875 lt 005) and in patients with the homozygous mutantallele of CYP1B1lowast2 (OR = 524 119875 lt 005) [21]

Although many polymorphisms of the CYP1B1 gene havebeen associated with different cancers less is known aboutchanges in mRNA expression levels in tumor tissue TheCYP1B1 gene encodes for amonooxygenase involved in phaseI of xenobiotic metabolism Levels of CYP1B1 mRNA varywidely fromdecreased levels inmesothelioma andmelanomato increased levels in prostate and nonsmall cell lung cancerHence CYP1B1 enzyme may be an antioncoprotein or anoncoprotein This depends on what pro-carcinogens are thefrequent cancer-causing agents in these tissue types andwhether CYP1B1 serves to activate or inactive them [111ndash114] Assessment of CYP1B1 expression levels in healthy andcancerous tissue types has been well studied Results showedthat CYP1B1 is upregulated in numerous cancers such asesophagus lung skin breast brain testis and colon cancers[115]HoweverCYP1B1has been detected at low levels in liverkidney brain and eye in healthy adult tissues [92 95 116]In a recent study Chi et al [39] evaluated CYP1B1 mRNAexpression in OSCC lines exposed to dibenz[a]pyrene andin healthy oral tissues from smokers and nonsmokers Theynoticed that the interindividual variation in inducibleCYP1B1expression may account in part for variation in tobacco-related OSCC risk Furthermore Schwartz et al [117] foundthat RNA from brush cytology of hamster oral SCC showeddifferential CYP1B1 expression in dibenz[a]pyrene-inducedOSCC Moreover Kolokythas et al [118] demonstrated adownregulation of CYP1B1 at the mRNA level only in OSCCfrom oral brush cytology samples Similar to Kolokythas et al[118] findings Pradhan et al [119] observed downregulationof CYP1B1 in cancerous tissues in comparison with theircorresponding healthy tissues as well as in the epithelialdysplasia lesion compared with its matched healthy tissueat the transcriptional level and in cancerous tissues at theprotein level [119] This difference might be due to differentkinds of oral lesions examined by Pradhan et al [119] andShatalova et al [120] However an upregulation of CYP1B1which included only 195 of oral lesions was observed in arecent HNSCC study [120] These contrasting observationsmight be due to differences between examined oral lesionsby Pradhan et al [119] and Shatalova et al [120] Levels ofCYP1B1 in oral tissue were approximately 2ndash4 folds higher insmokers than in nonsmokers according to a recent report byBoyle et al [121] In addition Sacks et al [122] stated that theapproximate level of 3ndash5 120583gmL of tobacco smoke particleswould enhance epithelial oral cells Thereby regarding tothe ability of tobacco smoke particles to induce CYP1B1 incultured human cells and hence in smoker oral tissue thereis a good correspondence between the established lower


concentration range in the Sacks et al [122] research andlevels in oral tissue in smokers

23 CYP2D6 Cytochrome P450s consist of the major en-zymes required for phase I metabolism of xenobioticsCytochrome P450 2D6 (CYP2D6) is one of the enzymesthat catabolize about 20 of commonly prescribed drugsCytochrome P450 2D6 has also a variety of activities amonghuman populations In fact the interindividual metabolismrates differ more than 10000 folds [123ndash125] Furthermorethe CYP2D6 gene is activated by some xenobiotic carcino-gens such as nicotine which is the major constituent oftobacco [126] Several predictive computer models have beenpublished in which the distance between a basic nitrogenatom and the site of oxidation in the substrates determineswhether a compound is metabolized by CYP2D6 or not[127] The CYP2D6 gene is localized on chromosome 22q131[128] The variant CYP2D6 alleles can be classified intocategories which cause catalytic activity abolish decrease tostay normal increase or to be qualitatively altered

Some of the known allelic variants of CYP2D6are not functional or have a reduced catalytic activity(httpwwwimmkisecypalleles) CYP2D6lowast4 (G1934A) isthe most common poor metabolizer (PM) in Caucasianshowever its frequency is very low in Asians [129 130]CYP2D6lowast3 (2549delA) CYP2D6lowast5 and CYP2D6lowast6(1707delT) are also frequent PMs in Caucasians Yet theywere described in a less frequency in the Asian population[129ndash131] CYP2D6lowast10 allele (C100T at exon 1) related toa reduced catalytic activity was found in 50 of the Asianpopulations and in 2 among Caucasians [129 130 132]

The role of the CYP2D6 gene as a risk factor fortobacco-related cancers has been extensively studied sinceearly reports suggested an association between the high-metabolizing CYP2D6 phenotype and HNC risk in smokers[28 133 134] However no association between CYP2D6genotype and smoking dose has been observed in terms ofrisk for UADT cancer in another study [29 76] RecentlyYadav et al [135] found a difference in the risk of developingHNSCC depending on the genotype In fact patients withCYP2D6lowast4 allele present an increased risk while those withCYP2D6lowast10 allele have no change or even a small decreasein risk in the Indian patients when comparison is donebetween consumers of tobacco or alcohol and nonconsumersThus CYP2D6 genotypes are not the only genetic factors thatinteract with environment in determining the susceptibilityto HNSCC Furthermore it was shown that patients withpoor metabolizer genotypes of CYP2D6 did not respond tothe treatment The fact that the majority of patients presenteither CYP2D6lowast4 or CYP2D6lowast10 genotypes indicates thatindividuals with PM genotypes of CYP2D6 are more proneto develop HNSCC [135] In addition it was reported thatCYP2D6 ultrarapid metabolizer patients from Spain andGermany have an increased risk to developHNSCC [75 136]Nevertheless patients with laryngeal SCC and breast cancerhave an increased frequency of PM genotypes [56 137]Theseobservations are consistent with previously reported results[138 139] However Kato et al [140] have reported thatpatients carrying inactivating alleles of theCYP2D6 gene have

reduced levels of DNA nitrosamine Caporaso et al [141]have demonstrated that CYP2D6 is not involved in nicotinedependency and hence this gene is not likely to have a majoreffect on tobacco smoking

24 CYP2E1 TheCYP2E1 human gene is located on chromo-some 10 (10q243-qter) contains 9 exons and encompassesseveral polymorphisms Some of them have an effect on theprotein expression [142] The CYP2E1 enzyme is responsiblefor the metabolism of alcohol and some tobacco carcinogenssuch as low-molecular weight nitrosamines [24 143 144]CYP2E1 enzyme activity is needed during the metabolicactivation ofmany carcinogens such as nitrosaminesCYP2E1is expressed in oral epithelial cell lines cultures in humanoral mucosa and in tongues of rats [145 146] Two linkedpolymorphisms (CYP2E1lowast5B) have been described in theCYP2E1 gene at nucleotides -1259 and -1019 They are locatedin the 51015840 regulatory region and are detectable by RsaI or PstIrestriction enzyme digestion [RsaI is 21053CgtT (rs2031920)and PstI is 21293GgtC (rs3813867) resp] [142 147] Accord-ing to the presence or absence of these two restrictionsites two alleles have been defined the common ldquowild-typerdquo allele (RasI+PstIminus) known as c1 and the variant allele(RasIminusPstI+) known as c2 It was suggested that the RasIpolymorphism located in a putative HNF-1 transcriptionfactor-binding site might play a role in the expression ofCYP2E1 [142] In fact in vitro studies have demonstrated thatthe regulatory region of the c2 homologous allele shows a sig-nificant increase in transcriptional acetyltransferase reportergene if compared with that of the c1 allele [142 148] It wasalso reported that the CYP2E1lowast6 polymorphism (rs6413432)is suspected to alter transcription of the CYP2E1 gene [149]

Over the last two decades several studies have exploredthe association of the CYP2E1 polymorphism with the riskof lung cancer [150] gastric cancer [151 152] and pancreaticcancer [154] Recently several studies on the associationbetween the CYP2E1 polymorphism and HNC have alsobeen published but those studies have yielded contradictoryresults Four separate epidemiological studies showed noassociation between the c2 allelic variant (RasIminusPstI+) andthe risk for UADT cancer in Brazilian [153] or Japanese [55]subjects Furthermore Cury et al [85] and Balaji et al [154]observed absence of any association with CYP2E1 PstI andHNC in Brazilian patients and oral cancer in South IndiansMoreover Gajecka et al [56] Tai et al [71] did not reveal anyassociation between the CYP2E1 RsaI polymorphism and theoverall risk of larynx cancer in Polish and Chinese patientsrespectively In addition other studies [53 55 134 155 156]have not found significant differences in allelic variantsin patients with HNSCC including oral cancer HoweverGajecka et al [56] found that RasIminusPstI+ variant allele wasmore frequent in controls (28) than in larynx cancer group(16) which may suggest that the mutated allele is ratherldquoprotectiverdquo These results are in agreement with the Swedishstudy which reported that individuals with RasIminusPstI+ allelemay be at lower risk for lung cancer [157] However theseresults are not consistent with previous studies conducted inthe Caucasian andChinese populations in which theCYP2E1


RasI SNP was shown to be associated with increased risk ofHNSCC OSCC and esophageal cancer [26 147 158ndash160]

Several Brazilian studies have explored the role ofCYP2E1polymorphisms in the induction of HNC A later study [68]on Brazilian patients withHNC indicated that the presence oftheRasIminusPstI+ variant allelewas associatedwith an increasedrisk of suffering specifically from oral cancer Furthermorein another Brazilian study of HNC [67] it was observedthat the CYP2E1lowast5Alowast5B (c1c2) genotype was more frequentin oral cavity tumors than in tumors from other anatomicsites (119875 = 0003) and that the CYP2E1lowast5Alowast5A (c1c1)genotype wasmore frequently detected in white patients (119875 =00031) A study including 289 Brazilian volunteers showedthat the frequencies of theCYP2E1lowast6 alleles (DraI rs6413432)are similar to those observed in Caucasians and African-Americans but the frequency of the CYP2E1lowast5B allele ishigher in Brazilians [161] However for the Brazilian pop-ulation taking into account the small number of nonwhiteindividuals conclusions were so limited Moreover ancestryinformative marker-based reports have concluded that at anindividual level in Brazil race is a poor predictor of genomicancestry [162 163]

The association between CYP2E1 (RsaIPstI) and CYP2E1(DraI) polymorphisms and HNC susceptibility has beenwidely investigated However results were inconsistentRecently Lu et al [164] and Tang et al [149] have assumedthat CYP2E1 (RsaIPstI) polymorphism might be a riskfactor for HNC in the Asian population as well as severalcarcinogenic processes that cpolymorphism might be a riskfactor

ould induce carcinogenesis In contrast to these findingsstudies conducted by Liu et al [165] on a Chinese popula-tion have concluded that there is no significant associationbetween CYP2E1 (RsaI or DraI) polymorphisms and suscep-tibility to esophageal SCC (OR = 167 119875 = 011 OR =111 119875 = 074 resp) Therefore it was suggested that c2allele and DD genotype represent a risk factor for esophagealSCC The frequencies of these two mutations in the Chinesepopulation [165] were all higher than those of the Caucasianpopulation which indicated the ethnic difference in the twopolymorphisms of CYP2E1 [166 167] Hence there might bea reliable efficiency to evaluate genetic susceptibility of RsaIandDraI polymorphisms for esophageal SCC in a populationwith high mutant frequencies

Tobacco and alcohol consumption represent the mostimportant factors for HNC hence genes involved in tobaccocarcinogen and alcohol metabolism should play a role in theHNC development An association between the c2 allele andthe increased oral cancer risk was previously demonstratedamong nonbetel quid chewing males from Taiwan [168]In addition in another Taiwanese study [169] the CYP2E1(c2c2) genotypewas found to be associatedwith an increasedNPC risk an effect most pronounced in non-smokersRecently Jia et al [170] found robust evidence for associationsbetween genetic variants of CYP2E1 and NPC risk in theCantonese population They observed that individuals agedless than 46 years and who had a history of cigarette smokingpresent OR of specific genotypes ranging from 188 to 299corresponding to SNPs rs9418990 rs1536826 rs3827688 and

rs8192780 (119875 = 00001ndash00140) Furthermore Liu et al [146]compared the risk of oral cancer between the Caucasian andAfrican-American patients depending on the genotypeTheyfound that patients with ldquowild-typerdquo (c1c1) genotype havean increased risk if compared with controls smoking lessthan 24 pack-years Nevertheless this association was absentfor patients with CYP2E1 genotypes among heavy smokersThese findings support the hypothesis that impact of geneticfactors in cancer risk is more reduced if carcinogen dosesare higher [171] A hospital-based study [172] of CYP2E1lowast5Band CYP2E1lowast6 polymorphisms and gene-environment inter-actions in the risk of UADT cancers among Indians wasconducted Results showed absence of differences betweengroups for the two polymorphisms if analyzed separatelyHowever results for CYP2E1lowast6 polymorphisms showed sig-nificant interactions among tobacco smokers (gt40 pack-years) and regular tobacco chewers These results illustratethe interaction between genes and environment and providean additional genetic risk factor CYP2E1lowast6 polymorphismsfor UADT cancers in the Indian population [172]

CYP2E1 metabolizes ethanol and generates reactive oxy-gen species and it has been suggested that it is importantfor the development of alcoholic liver disease and cancerincluding hepatoblastoma and HNC Acetaldehyde dehy-drogenases are a group of NAD-dependent enzymes whichcatalyze the oxidation of acetaldehyde being the secondenzyme of the alcohol oxidation pathway (Figure 2) [27 173]Levels of CYP2E1 are elevated under a variety of physiologicand pathophysiologic conditions and after acute and chronicalcohol exposure [174 175] Interestingly in a recent Chinesestudy of Guo et al [160] the polymorphism of CYP2E1lowast5Bgene (c2c2 genotype) and alcohol consumption and werefound to increase the risk of OSCC (119875 lt 001 OR = 246and 95 CI = 178ndash404) In addition in the study of Olivieriet al [67] among alcohol users the CYP2E1lowast5B variant allelewas more frequently detected in HNC Brazilian patients thanin control subjects (119875 lt 00001 OR = 1906 and 95 CI =2450ndash1483) Overall the data suggested that CYP2E1lowast5B isan independent biomarker of risk in alcohol-related HNCRecently Cury et al [85] confirmed that smoking andalcohol consumption were risk factors for HNC but theCYP2E1lowast6 and CYP2E1lowast5B polymorphisms investigated hadno association with the development of HNC in Brazilianpatients Alcohol or tobacco consumptions were also foundto interact with variant genotypes of CYP2E1 in significantlyenhancing HNC risk [147] In addition it was suggested thatCYP2E1lowast5B polymorphism can be quite important in oralcarcinogenesis in Brazilians [53] or can be compensated byother genes involved in the ethanol and other carcinogensmetabolism in oral mucosa [53] Absence of associationbetween CYP2E1lowast5B polymorphism and lung cancer amongpatients from Rio de Janeiro has been previously observed[155] this could be explained by the fact that alcohol is nota lung carcinogen

The difference in the genetic background between dif-ferent ethnicities associated to other genetic factors involvedin the etiology of HNC might be behind the variability andthe inconsistency of these results It is well established theinvolvement of some genetic polymorphisms if combined


C C C C CH

H

H H

H H

HHH

H

HHOH

C CH

H

H H

OH

OH

OH

Ethanol

ADH

NAD+ NADH++ H+ NAD+

+ H2O

ALDH

Acetaldehyde Acetic acid

NADPH++ H+

+ O2

Ethanediol

H2O

NADP++ H2O

OC

O

CYP2E1

NADH + H+

Figure 2 Alcohol metabolism [173]

Human NATI gene expression control

Promoters Tissue-specific P3 (a)minus516 kb

Constitutive P1 (b)minus119 kb

Proximal P0minus025 kb

(not to scale)

Poly Al A2

1 2 3 4 5 6 7 8 ORF

Transcription elements and factors (evidence)

Sp1 binding site (sequence similarity)

Androgen-responsive region (deletion analysis)

YY-1 (EMSA)AP-1 (PMA sensitive)AhR (sequence similarity xenobiotic inducible)

GenomicDNA

CCAATTCATT box (sequence similarity)

(a)

NCE at minus87 kb ORF Poly Al A2GenomicDNA


AP-l (sequence similarity)

Human NAT2 gene

TATA box (sequence similarity)

(b)

Figure 3 Human NAT genes (a) NAT1 and (b) NAT2 [176 177]

with smoking and alcohol metabolism in the developmentof HNC The risk is higher than the tobacco and alcoholconsumption is immense Regarding the genetic componentits effect is depending on the allele combination Furtherpopulation genetic studies focusing on metabolizing enzymepolymorphisms should be very helpful in clarifying theindividual genetic susceptibility and hence offer the adequateand personalized management of the patient

3 Arylamine N-Acetyltransferases (NATs)

NAT1 and NAT2 human isoforms are encoded by twogenes with intronic less coding regions The NAT genes are

located on chromosome 8p213ndash231 and express two highlypolymorphic isoenzymes (NAT1 and NAT2) with distinctfunctional roles In humans the products of these two genesappear to have distinct functional roles depending on theirsubstrate their expression in tissues and the expression of thedifferent genes during development Although the two genesare organized in a single open-reading frame their structureand control vary markedly (Figure 3) [176 177] Recentstudies on human NAT1 and NAT2 genes have identifiedinteractions within the active site cleft that are crucial forsubstrate recognition [178] The specific recognition of thesubstrate is provided by the C-terminal region of the NATproteins [179] mainly by residues around positions 124ndash129[180]


minus5

lowast4

lowast4

lowast4

lowast4

lowast4

lowast5

B

lowast5

B

lowast6

A

lowast6

A

lowast4

lowast6

A

lowast10

lowast10

a

lowast10

b

1 2 3 4 5 6 7 8 9

0

5

10

15

20

25

30

35

40

Odd

s rat

io

lowast5

Blowast5

B

Figure 4 Odds ratios (OR) for HNCs from one NAT1 and eightNAT2 studies Bars indicate 95 confidence intervals (CI) whileindividual SNPs in each study are labeled for each vertical line andstudy numbers are indicated at the bottom (NAT2 (1 [53] 2 [195]3 [197] 4 [198] 5 [194] 6 [193] 7 [56] 8 [133] NAT1 9 [199])aSmokers bnonsmokers

N-Acetyltransferases are involved in the metabolism ofcertain carcinogens responsible for tumors in rodents likearomatic and heterocyclic amine carcinogens [181] Based ongenetic engineering a critical cysteine (amino acid 68) withinthe catalytic sitewas createdThis catalytic site is implicated inacetyl transfer between the acetyl-CoA cofactor and acceptorsubstrates [182] The latter could be aromatic amines andhydrazines (N-acetylation) or N-hydroxy-aromatic and N-heterocyclic amines (O-acetylation) The substrate could beactivated or deactivated byNAT1 andorNAT2 ifO-acetylatedor N-acetylated respectively [183] Because these two genesare involved in metabolic activation via O-acetylation [184ndash187] their genetic polymorphisms could modify the can-cer susceptibility related to carcinogen exposure Many N-hydroxy heterocyclic amine carcinogens are catalyzed byhuman NAT2 than NAT1 [185 187] Their tissue-specificexpression is also a determinant factor for a better efficiency

So far 36 NAT2 genetic variants have been identifiedin human Among them NAT2lowast4 is the most commonallele reported to be associated with rapid acetylation [188]The other alleles are classified into two groups the rapidalleles that includeNAT2lowast11ANAT2lowast12A-CNAT2lowast13A andNAT2lowast18 and the slow alleles such as NAT2lowast5 NAT2lowast6 andNAT2lowast7 For NAT1 the most common alleles are NAT1lowast3NAT1lowast4NAT1lowast10 andNAT1lowast11NAT1lowast4 is themost commonallele while NAT1lowast10 is the putative rapid allele Subjectshaving more than one rapid allele were designated by NAT1rapid acetylation For the others they were classified underNAT1 slow acetylation [188]

As NAT1 and NAT2 genes are characterized by allelicheterogeneity several haplotypes have been establishedTheywere associated with either the rapid or the slow acetylatorphenotype [133] All SNPs of both genes (slow and rapidalleles) have been associated with an increased risk of cancerThis association could be explained by their ability to detoxifyaromatic amine carcinogens from one hand and to producehigher levels of reactivemetabolites from another hand [189]In 1987 Drozdz et al [190] had established an association

between the slow acetylator phenotype and the increased riskfor laryngeal cancer So far little is known about the role of theNAT gene SNPs and their association with HNC (Figure 4)

Some studies have reported that alteration of NATenzyme activity might be of risk for UADT cancer It waspreviously shown that patients with NAT2 slow acetylatorgenotypes (homozygous for NATlowast5 NATlowast6 and NAT2lowast7alleles) are significantly (119875 lt 0002) more prone todevelop UADT cancer (037) as compared with controls(022) [133] In a recent study on the Turkish population theslow acetylator NAT2lowast7 allele was correlated to a reducedUADT cancer risk [191] as well as larynx cancer [192] thussuggesting a protective role of NAT2lowast7 genotype in HNCNAT2lowast5 and NAT2lowast6 alleles seem to be associated withcancer risk [191] Studies focusing on NAT2 haplotypes haveshown an association betweenNAT2lowast4 andHNC [191]Theseresults support the hypothesis of the possible involvement ofNAT2lowast4 combinations (NAT2lowast4lowast6A) in larynx cancer pre-disposition (OR = 324 119875 = 0045) [56] In a Tunisian studyBendjemana et al [193] observed that genotypic frequenciesof NAT2lowast6NAT2lowast6 were significantly higher in the group ofnasopharyngeal carcinoma patients (OR = 614 95 IC =24ndash140) Furthermore in another Tunisian study [194]a significant difference was found between HNC patientsand controls for T341C mutation (NAT2lowast5 rs1801280) inNAT2 gene (OR = 182 119875 = 004) This finding is inaccordance with the reported association between squamouscell carcinoma and T341C mutation [133] This is probablydue to the great reduction in acetyltransferase 2 catalyticactivity in relation with the T341C mutation (NAT2lowast5) inNAT2 gene [189] However no significant difference wasfound between HNC Tunisian patients and controls forG590A (NAT2lowast6) mutation in NAT2 gene [194] In additionno association between the NAT2 genotype and NPC wasfound in the Taiwanese population [77]

An association was found between the homozygousNAT2lowast4 allele and the increased oral cancer risk in a Brazilianpopulation (OR = 195 119875 = 0032) [53] Likewisemany studies have reported an association between rapidacetylator phenotype and the increased risk of oral andlaryngeal cancer in Caucasians [195 196] At the biologicallevel this could be explained by the fact thatO-acetylation ofnitrosamines byNAT2 could be more important as a negativemetabolic pathway leading to oral carcinogenesis thereforeslow acetylators would be protected Chatzimichalis et al[197] established the distribution of genotypes and showedthat it consisted of 5568 of rapid acetylators and 4432of slow acetylators in laryngeal SCC patients while it was of3627 of rapid acetylators and 6372 of slow acetylatorsin controls This study [197] concluded that rapid acetylatorgenotypes are significantly associated to laryngeal SCC in theGreek population (OR = 2207 119875 = 00087) FurthermoreBuch et al [198] found that fast acetylators (NAT2lowast4) aremore frequent in oral cancer patients (537) than in controls(439 OR = 155 95CI = 108ndash220 119875 = 003)

Several studies have explored the role of NAT1 poly-morphisms in the incidence of HNC The first study [199]was conducted to test the oral cancer risk associated withpolymorphism in the NAT1 gene This study is still until now


Table 2 Summary of studies on CYPs450 and NATs genes status in HNC

Gene Population 119873 (casecontrol) SNP (allele or genotype) OR 95 CI 119875 value References

CYP1A1

Japanese 100100 lowast2Alowast2A 36 14ndash95 lt005 [69]

Indian mdashlowast1Alowast2A 176 119ndash260 mdash [66]lowast2Alowast2A 283 143ndash561 mdash

Indian 458729 m2m2 32 110ndash1028 005 [64]Korean 72221 m2m2 38 19ndash77 0023 [63]Brazilian 153145 lowast1Alowast2A mdash mdash 0003 [67]Japanese 142142 m2m2 23 11ndash47 lt005 [54]

Indian 408220 MspIa+ 643 369ndash1121 lt005 [65]MspIc+ 1024 595ndash1760 lt005

Brazilian 103102 MspI+ 24 113ndash510 mdash [68]Indian 203201 T3801C 489 315ndash732 lt001 [89]Japanese 145164 lowast2Alowast2A 41 11ndash15 0038 [55]Chinese 278278 3798 CC 239 111ndash516 0027 [71]

Indian 205245m1m1 812 327ndash2130 0000002

[79]w1m1 196 114ndash338 00092m2m2 631 224ndash1869 0000015

Polish 289316 lowast4lowast4 170 099ndash288 0049 [56]Caucasian (meta-analysis) mdash 129 105ndash165 mdash [70]

22 studies (meta-analysis) 41684638 MspI+ mdash 115ndash157 lt0001 [59]MspIa 298 169ndash526 lt0001

CYP1B1Indian 150150

lowast2 (wtmt) 236 127ndash438 004

[21]

lowast2 (mtmt) 334 120ndash936 003lowast2 (wtmt)a 237 162ndash485

lt005lowast2 (wtmt or mtmt)a 447 207ndash960lowast2 (wtmt or mtmt)c 881 260ndash2987 lt005lowast3 (wtmt or mtmt)c 274 112ndash670 lt005

German 195177 lowast3a f 453 262ndash798 lt0001 [26]

CYP2D6Indian 350350

lowast4 (mtmt) 232 114ndash434 lt0001[135]lowast10 (wtmt) 206 148ndash287 lt0001

lowast10 (mtmt) 185 119ndash289 lt0001Polish 289316 lowast4lowast4 (1934GG) 236 103ndash539 0045 [56]

CYP2E1

Brazilian 153145 lowast5B 1906 2450ndash1483 lt00001 [67]Chinese 320320 lowast5B 246 178ndash404 lt001 [160]

Indian mdashlowast5B 344 145ndash814 mdash [147]lowast6 176 145ndash241 mdash

German 312299 minus71 GgtT 049 025ndash098 004 [159]

Chinese 755755

rs9418990d 295 168ndash517 00002

[170]rs8192780d 299 172ndash521 00001rs1536826d 294 169ndash513 00001rs3827688d 188 113ndash313 00140

CaucasianAfrican-American 113226 c1c1e mdash mdash 0033[146]

58173

24 studies (meta-analysis) 12562mdash

lowast5B[164]c2 allele 111 100ndash122 004

c2c2 157 114ndash215 000617 studies (meta-analysis) 16632603 c1c2 064 050ndash081 lt0001 [158]24 studies (meta-analysis) 12562 (all) c2c2 157 114ndash215 0006 [206]


Table 2 Continued


21 studies (meta-analysis) 49516071lowast5B 196 133ndash290 lt005

[93]lowast6 156 106ndash227 lt005

Asian (meta-analysis) 49516071lowast5B 204 132ndash315 lt005

[93]lowast6 204 127ndash329 lt005

NAT1 Japanese 62122

lowast10 372 156ndash890 lt001[199]lowast10a 314 109ndash907 0017

lowast10b 588 113ndash306 0022

NAT2

Brazilian 231212 lowast4lowast4 195 105ndash360 0035 [53]German 255510 lowast4 218 113ndash422 0018 [195]Greek 88102 lowast4 220 123ndash395 00087 [197]

American (USA) 203416 lowast4 155 108ndash220 003 [198]Tunisian 64160 lowast5B 182 268ndash1226 004 [194]Tunisian 45100 lowast6A 614 24ndash14 lt005 [193]

Polish 289316lowast4lowast6A 324 11ndash975 0045 [56]lowast5Blowast5B 341 16ndash99 0043

Spanish75200

lowast6A 030 010ndash089 lt0042[133]

lowast5B 048 025ndash093 lt0039145164 mdash 2 mdash 0039 [55]

aSmokers bnonsmokers cchewers dsmokers lt46 years esubjects smoked lt24 pack-years fcalculation for wtwt genotype versus wtmt and mtmt genotypesmdash undefined + the genotypeallele undefined

the only one that suggested a significant increased risk (OR =372 119875 lt 001) associated with the NAT1lowast10 allele in theJapanese population [199] However the other studies havesuggested negative findings [191 195 200 200]

Gene-gene interaction testing has shown several cancer-NAT2 associations The strongest one was observed amongpersons without a CYP1A1 variant (lowast2C or lowast4) allele (OR =177 95 CI = 120ndash260 and 119875 = 003) [198] Theseresults implicate fastNAT2 acetylation as a risk factor for oralcancer in the American population (USA) [198] MoreoverDemokan et al [191] and McKay et al [201] found thatthe association with NAT1 and NAT2 gene combinationsmay influence the risk of developing HNC A signifi-cant association was observed between the fast acetylatorNAT2lowast4NAT1lowast10 diplotype and risk ofHNC [191]Moreoverthe association with NAT1lowast11NAT2lowast6A haplotypes was cor-related to the risk of UADT cancer (OR = 154 119875 = 003)[201]

NAT gene presents a crucial role in the detoxification andactivation reactions of numerous xenobiotics originating notonly from tobacco-derived aromatic and heterocyclic aminecarcinogens but also from drug metabolism Its functionis undergone through N- and O-acetylation pathways [200202] via a ping-pong bi-bi mechanism The initial stepconsists on acetylation of Cys68 by an acetyl-coenzymeA along with the release of the cofactor product coen-zyme A Secondly the substrate is linked to the acetylatedenzyme Finally the acetylated product is released [203]Since chemical compounds present in tobacco are inactivatedby phase II enzymes it has been proposed that HNC riskcould be modified by NAT genotypes HNCs are stronglyassociated with smoking and a few studies have exploredthe role of NAT1 polymorphisms in the risk of developing

HNC in smokers [199 204] However overall findings areinconsistent and associations if present are weak and indicateeither a decreased risk in carriers of the variant NAT1 [201]an increased risk [205] or a lack of association [191 195 200202]

The role of NAT1 and NAT2 acetylator polymorphisms incancer risk from aromatic and heterocyclic amine carcino-gens will become clearer with more precise determinationsof both exposures and genotypes Further studies of thehaplotype combinations in different populations and withlarger cohorts are warranted to determine the range of risksassociated with the effect of genetic variation of the NATgenes with regard to HNC

4 Conclusion

The present paper reviews studies that assessed associa-tion between genetic polymorphisms of genes encodingcarcinogen-metabolizing enzymes and showed their possibleinvolvement by significantly increasing the predispositionfor HNC This risk relies on many factors such as the levelof carcinogen exposure (eg tobacco smoke) the ethnicityandor racial groups and so forth Various polymorphisms inthese genes are summarized in Table 2Many of the discussedstudies described HNC risk for a mixed racial andor ethniccohort As shown previously cancer susceptibility is differentaccording to the genotype in a given racial group Thus evenif cases and controls are race-matched erroneous associationmight be taken into consideration if different racial andorethnic groups are mixed In addition differences in geneticbackgrounds formetabolic genotypes between races and evenbetween ethnic groups whether located in the same region


or not should also be taken into consideration before anassociation study is performed Furthermore metabolizingenzyme expression could widely vary at diverse sites withinthe head and neck

It is well known that there is a real logistical difficultythat consists in combating at least one of the potentialbiases listed above However careful attention should begiven to all elements before conducting an associationstudy in order to ensure accurate and significant results Ifwell designated these studies would clarify the impact ofxenobiotic-metabolizing enzymes in HNC development andhelp determine the value of potentially ldquohigh-riskrdquo genotypesin HNC prevention strategies

Abbreviations

CYP450 Cytochrome P450HNSCC Head and neck squamous cell carcinomaNPC Nasopharyngeal cancerOR Odds ratiosOSCC Oral squamous cell carcinomaNAT Arylamine N-acetyltransferasePM Poor metabolizerSCC Squamous cell carcinomaSNP Single-nucleotide polymorphismTSNAs Tobacco-specific nitrosaminesUADT Upper aerodigestive tract

Conflict of Interests

The authors declare that they have no conflict of interests

Acknowledgment

The authors wish to gratefully acknowledge Adouni Tawfik(Chairman of Federal Consulting amp Language Services LLCTampa FL USA) for his assistance in the English revision ofthis paper

References

[1] J F Gallegos-Hernandez ldquoLymphatic mapping and sentinelnode biopsy in squamous cell carcinoma of head and neckmucosardquo Cirugia y Cirujanos vol 74 no 3 pp 167ndash173 2006

[2] N Penel E Y Amela YMallet et al ldquoA simple predictivemodelfor postoperative mortality after head and neck cancer surgerywith opening of mucosardquoOral Oncology vol 43 no 2 pp 174ndash180 2007

[3] L Mao W K Hong and V A Papadimitrakopoulou ldquoFocuson head and neck cancerrdquo Cancer Cell vol 5 no 4 pp 311ndash3162004

[4] E M Sturgis Q Wei and M R Spitz ldquoDescriptive epidemi-ology and risk factors for head and neck cancerrdquo Seminars inOncology vol 31 no 6 pp 726ndash733 2004

[5] S A Frank ldquoGenetic variation in cancer predisposition muta-tional decay of a robust genetic control networkrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 101 no 21 pp 8061ndash8065 2004

[6] P Vineis M Alavanja P Buffler et al ldquoTobacco and cancerrecent epidemiological evidencerdquo Journal of theNational CancerInstitute vol 96 no 2 pp 99ndash106 2004

[7] H Viswanathan and J A Wilson ldquoAlcoholmdashthe neglected riskfactor in head and neck cancerrdquo Clinical Otolaryngology andAllied Sciences vol 29 no 4 pp 295ndash300 2004

[8] P P Hakim ldquoHead and neck cancermdashthe Indian scenerdquo Inter-national Congress Series vol 1240 pp 973ndash984 2003

[9] P Brennan and P Boffetta ldquoMechanistic considerations inthe molecular epidemiology of head and neck cancerrdquo IARCScientific Publications no 157 pp 393ndash414 2004

[10] W Y Huang A F Olshan S M Schwartz et al ldquoSelectedgenetic polymorphisms in MGMT XRCC1 XPD and XRCC3and risk of head and neck cancer a pooled analysisrdquo CancerEpidemiology Biomarkers and Prevention vol 14 no 7 pp 1747ndash1753 2005

[11] M Ingelman-Sundberg ldquoGenetic variability in susceptibilityand response to toxicantsrdquo Toxicology Letters vol 120 no 1ndash3pp 259ndash268 2001

[12] W Garavello R Foschi R Talamini et al ldquoFamily history andthe risk of oral and pharyngeal cancerrdquo International Journal ofCancer vol 122 no 8 pp 1827ndash1831 2008

[13] E Negri P Boffetta J Berthiller et al ldquoFamily history of cancerpooled analysis in the International Head and Neck CancerEpidemiology consortiumrdquo International Journal of Cancer vol124 no 2 pp 394ndash401 2009

[14] A Baez ldquoGenetic and environmental factors in head and neckcancer genesisrdquo Journal of Environmental Science and Health Cvol 26 no 2 pp 174ndash200 2008

[15] A F Olshan M C Weissler M A Watson and D A BellldquoGSTM1 GSTT1 GSTP1 CYP1A1 and NAT1 polymorphismstobacco use and the risk of head and neck cancerrdquo CancerEpidemiology Biomarkers and Prevention vol 9 no 2 pp 185ndash191 2000

[16] G Matullo D Palli M Peluso et al ldquoXRCC1 XRCC3 XPDgene polymorphisms smoking and 32P-DNA adducts in asample of healthy subjectsrdquo Carcinogenesis vol 22 no 9 pp1437ndash1445 2001

[17] N Jourenkova M Reinikainen C Bouchardy P Dayer SBenhamou and A Hirvonen ldquoLarynx cancer risk in relationto glutathione S-transferase M1 and T1 genotypes and tobaccosmokingrdquoCancer Epidemiology Biomarkers and Prevention vol7 no 1 pp 19ndash23 1998

[18] H Bartsch U Nair A Risch M Rojas H Wikman and KAlexandrov ldquoGenetic polymorphism of CYP genes alone orin combination as a risk modifier of tobacco-related cancersrdquoCancer Epidemiology Biomarkers and Prevention vol 9 no 1pp 3ndash28 2000

[19] T T Sreelekha K Ramadas M Pandey G Thomas K RNalinakumari and M R Pillai ldquoGenetic polymorphism ofCYP1A1 GSTM1 and GSTT1 genes in Indian oral cancerrdquo OralOncology vol 37 no 7 pp 593ndash598 2001

[20] P P Shah A P Singh M Singh et al ldquoInteraction ofcytochrome P4501A1 genotypes with other risk factors andsusceptibility to lung cancerrdquo Mutation Research vol 639 no1-2 pp 1ndash10 2008

[21] A P Singh P P Shah N Mathur J T M Buters M CPant and D Parmar ldquoGenetic polymorphisms in CytochromeP4501B1 and susceptibility to Head andNeck CancerrdquoMutationResearch vol 639 no 1-2 pp 11ndash19 2008


[22] S S Yadav M Ruwali P P Shah et al ldquoAssociation of poormetabolizers of cytochrome P450 2C19 with head and neckcancer and poor treatment responserdquo Mutation Research vol644 no 1-2 pp 31ndash37 2008

[23] A P Singh P P Shah M Ruwali N Mathur M C Pant and DParmar ldquoPolymorphism in cytochrome P4501A1 is significantlyassociatedwith head andneck cancer riskrdquoCancer Investigationvol 27 no 8 pp 869ndash876 2009

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[25] S S Hecht ldquoTobacco carcinogens their biomarkers andtobacco-induced cancerrdquo Nature Reviews Cancer vol 3 no 10pp 733ndash744 2003

[26] Y Ko J Abel V Harth et al ldquoAssociation of CYP1B1 codon 432mutant allele in head and neck squamous cell cancer is reflectedby somatic mutations of p53 in tumor tissuerdquo Cancer Researchvol 61 no 11 pp 4398ndash4404 2001

[27] W Jelski and M Szmitkowski ldquoAlcohol dehydrogenase (ADH)and aldehyde dehydrogenase (ALDH) in the cancer diseasesrdquoClinica Chimica Acta vol 395 no 1-2 pp 1ndash5 2008

[28] C Matthias U Bockmuhl V Jahnke et al ldquoPolymorphism incytochrome P450 CYP2D6 CYP1A1 CYP2E1 and glutathioneS-transferase GSTM1 GSTM3 GSTT1 and susceptibility totobacco-related cancers studies in upper aerodigestive tractcancersrdquo Pharmacogenetics vol 8 no 2 pp 91ndash100 1998

[29] S F Worrall M Corrigan A High et al ldquoSusceptibilityand outcome in oral cancer preliminary data showing anassociation with polymorphism in cytochrome P450 CYP2D6rdquoPharmacogenetics vol 8 no 5 pp 433ndash439 1998

[30] S J Roberts-Thomson M E McManus R H Tukey F FGonzalez and G M Holder ldquoThe catalytic activity of fourexpressed human cytochrome P450s towards benzo[a]pyreneand the isomers of its proximate carcinogenrdquo Biochemical andBiophysical Research Communications vol 192 no 3 pp 1373ndash1379 1993

[31] J P Butler G B Post P J Lioy and JMWaldman ldquoAssessmentof carcinogenic risk from personal exposure to benzo(a)pyrenein the Total Human Environmental Exposure Study (THEES)rdquoJournal of the Air and Waste Management Association vol 43no 7 pp 970ndash977 1993

[32] J P Whitlock Jr S T Okino L Dong et al ldquoInduction ofcytochrome P4501A1 a model for analyzing mammalian genetranscriptionrdquo FASEB Journal vol 10 no 8 pp 809ndash818 1996

[33] S H Cherng P Lin J L Yang S L Hsu and HLee ldquoBenzo[ghi]perylene synergistically transactivatesbenzo[a]pyrene-induced CYP1A1 gene expression by arylhydrocarbon receptor pathwayrdquo Toxicology and AppliedPharmacology vol 170 no 1 pp 63ndash68 2001

[34] IARC ldquoPolynuclear aromatic compounds chemical environ-mental and experimental datardquo in Monographs on the Evalua-tion of the Carcinogenic Risk of Chemicals to Humans vol 32part 1 IARC Scientific Publications Lyon France 1983

[35] K Kawajiri CYP1A1 vol 148 IARC Scientific PublicationsLyon France 1999

[36] D W Nebert T P Dalton A B Okey and F J GonzalezldquoRole of aryl hydrocarbon receptor-mediated induction of theCYP1 enzymes in environmental toxicity and cancerrdquo Journal ofBiological Chemistry vol 279 no 23 pp 23847ndash23850 2004

[37] C Canova L Richiardi F Merletti et al ldquoAlcohol tobaccoand genetic susceptibility in relation to cancers of the upper

aerodigestive tract in northern Italyrdquo Tumori vol 96 no 1 pp1ndash10 2010

[38] N S Nagaraj S Beckers J K Mensah S Waigel NVigneswaran and W Zacharias ldquoCigarette smoke condensateinduces cytochromes P450 and aldo-keto reductases in oralcancer cellsrdquoToxicology Letters vol 165 no 2 pp 182ndash194 2006

[39] A C Chi K Appleton J B Henriod et al ldquoDifferentialinduction of CYP1A1 and CYP1B1 by benzo[a]pyrene in oralsquamous cell carcinoma cell lines and by tobacco smoking inoral mucosardquo Oral Oncology vol 45 no 11 pp 980ndash985 2009

[40] X Wen and T Walle ldquoPreferential induction of CYP1B1 bybenzo[a]pyrene in human oral epithelial cells impact on DNAadduct formation and prevention by polyphenolsrdquo Carcinogen-esis vol 26 no 10 pp 1774ndash1781 2005

[41] K Kawajiri H Eguchi K Nakachi T Sekiya and MYamamoto ldquoAssociation of CYP1A1 germ line polymorphismswithmutations of the p53 gene in lung cancerrdquoCancer Researchvol 56 no 1 pp 72ndash76 1996

[42] S F Zhou J P Liu and B Chowbay ldquoPolymorphism ofhuman cytochrome P450 enzymes and its clinical impactrdquoDrugMetabolism Reviews vol 41 no 2 pp 89ndash295 2009

[43] K Kawajiri K Nakachi K Imai J Watanabe and S HayashildquoThe CYP1A1 gene and cancer susceptibilityrdquo Critical Reviewsin OncologyHematology vol 14 no 1 pp 77ndash87 1993

[44] X Xu K T Kelsey J K Wiencke J C Wain and D CChristiani ldquoCytochrome P450 CYP1A1 MspI polymorphismand lung cancer susceptibilityrdquo Cancer Epidemiology Biomark-ers and Prevention vol 5 no 9 pp 687ndash692 1996

[45] K Nakachi K Imai S I Hayashi and K Kawajiri ldquoPoly-morphisms of the CYP1A1 and glutathione S-transferase genesassociated with susceptibility to lung cancer in relation tocigarette dose in a Japanese populationrdquo Cancer Research vol53 no 13 pp 2994ndash2999 1993

[46] I Cascorbi J Brockmoller and I Roots ldquoA C4887A poly-morphism in exon 7 of human CYP1A1 population frequencymutation linkages and impact on lung cancer susceptibilityrdquoCancer Research vol 56 no 21 pp 4965ndash4969 1996

[47] J Y Park J E Muscat Q Ren et al ldquoCYP1A1 and GSTM1polymorphisms and oral cancer riskrdquo Cancer EpidemiologyBiomarkers and Prevention vol 6 no 10 pp 791ndash797 1997

[48] N Ishibe S E Hankinson G A Colditz et al ldquoCigarettesmoking cytochrome P450 1A1 polymorphisms and breastcancer risk in the Nursesrsquo Health Studyrdquo Cancer Research vol58 no 4 pp 667ndash671 1998

[49] N Ishibe J K Wiencke Z F Zuo A McMillan M Spitz andK T Kelsey ldquoSusceptibility to lung cancer in light smokers asso-ciated with CYP1A1 polymorphisms in Mexican- and African-Americansrdquo Cancer Epidemiology Biomarkers and Preventionvol 6 no 12 pp 1075ndash1080 1997

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[51] S Garte ldquoThe role of ethnicity in cancer susceptibility genepolymorphisms the example of CYP1A1rdquo Carcinogenesis vol19 no 8 pp 1329ndash1332 1998

[52] H Inoue C Kiyohara T Marugame et al ldquoCigarette smokingCYP1A1 MspI and GSTM1 genotypes and colorectal adeno-masrdquo Cancer Research vol 60 no 14 pp 3749ndash3752 2000


[53] C F S Marques S Koifman R J Koifman P Boffetta PBrennan and A Hatagima ldquoInfluence of CYP1A1 CYP2E1GSTM3 and NAT2 genetic polymorphisms in oral cancersusceptibility results from a case-control study in Rio deJaneirordquo Oral Oncology vol 42 no 6 pp 632ndash637 2006

[54] M Sato T Sato T Izumo and T Amagasa ldquoGenetically highsusceptibility to oral squamous cell carcinoma in terms ofcombined genotyping of CYP1A1 and GSTM1 genesrdquo OralOncology vol 36 no 3 pp 267ndash271 2000

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[56] M Gajecka M Rydzanicz R Jaskula-Sztul M Kujawski WSzyfter and K Szyfter ldquoCYP1A1 CYP2D6 CYP2E1 NAT2GSTM1 and GSTT1 polymorphisms or their combinations areassociated with the increased risk of the laryngeal squamouscell carcinomardquoMutation Research vol 574 no 1-2 pp 112ndash1232005

[57] E Reszka P Czekaj J Adamska and W Wasowicz ldquoRelevanceof glutathione S-transferase M1 and cytochrome P450 1A1genetic polymorphisms to the development of head and neckcancersrdquo Clinical Chemistry and Laboratory Medicine vol 46no 8 pp 1090ndash1096 2008

[58] R Amtha C S Ching R Zain et al ldquoGSTM1 GSTT1 andCYP1A1 polymorphisms and risk of oral cancer a case-controlstudy in Jakarta Indonesiardquo Asian Pacific Journal of CancerPrevention vol 10 no 1 pp 21ndash26 2009

[59] L Liu G Wu F Xue et al ldquoFunctional CYP1A1 geneticvariants alone and in combination with smoking contributeto development of head and neck cancersrdquo European Journal ofCancer vol 49 no 9 pp 2143ndash2151 2013

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upper aerodigestive tract cancers in an Indian populationrdquoHead and Neck vol 30 no 12 pp 1566ndash1574 2008

[67] E H R Olivieri S D da Silva F F Mendonca et alldquoCYP1A2lowast1C CYP2E1lowast5B and GSTM1 polymorphisms arepredictors of risk and poor outcome in head andneck squamouscell carcinoma patientsrdquo Oral Oncology vol 45 no 9 pp e73ndashe79 2009

[68] G J Figaro Gatta M B de Carvalho M S Siraque et alldquoGenetic polymorphisms of CYP1A1 CYP2E1 GSTM-1 andGSTT1 associated with head and neck cancerrdquo Head and Neckvol 28 no 9 pp 819ndash826 2006

[69] K Tanimoto S I Hayashi K Yoshiga and T IchikawaldquoPolymorphisms of the CYP1A1 and GSTM1 gene involved inoral squamous cell carcinoma in association with a cigarettedoserdquo Oral Oncology vol 35 no 2 pp 191ndash196 1999

[70] W L Zhuo YWang X L Zhuo B Zhu Y Zhu and Z T ChenldquoPolymorphisms of CYP1A1 and GSTM1 and laryngeal cancerrisk evidence-based meta-analysesrdquo Journal of Cancer Researchand Clinical Oncology vol 135 no 8 pp 1081ndash1090 2009

[71] J Tai M Yang X Ni et al ldquoGenetic polymorphisms incytochrome P450 genes are associated with an increased riskof squamous cell carcinoma of the larynx and hypopharynx ina Chinese populationrdquo Cancer Genetics and Cytogenetics vol196 no 1 pp 76ndash82 2010

[72] M B Oude Ophuis E M Van Lieshout H M Roelofs W HPeters and J J Manni ldquoGlutathione S-transferase M1 and T1and cytochrome P4501A1 polymorphism in relation to the riskfor benign and malignant head and neck lesionsrdquo Cancer vol82 no 5 pp 936ndash943 1998

[73] W P Bennett M C R Alavanja B Blomeke et al ldquoEnvi-ronmental tobacco smoke genetic susceptibility and risk oflung cancer in never-smoking womenrdquo Journal of the NationalCancer Institute vol 91 no 23 pp 2009ndash2014 1999

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[75] S Gronau D Koenig-Greger M Jerg and H RiechelmannldquoGene polymorphisms in detoxification enzymes as susceptibil-ity factor for head and neck cancerrdquo Otolaryngology vol 128no 5 pp 674ndash680 2003

[76] V Jahnke C Matthias A Fryer and R Strange ldquoGlutathioneS-transferase and cytochrome-P-450 polymorphism as riskfactors for squamous cell carcinoma of the larynxrdquo AmericanJournal of Surgery vol 172 no 6 pp 671ndash673 1996

[77] Y J Cheng Y C Chien A Hildesheim et al ldquoNo associationbetween genetic polymorphisms of CYP1A1 GSTM1 GSTT1GSTP1 NAT2 and nasopharyngeal carcinoma in TaiwanrdquoCancer Epidemiology Biomarkers and Prevention vol 12 no 2pp 179ndash180 2003

[78] Y F Xu Q H Pan C Cui et al ldquoAssociation of nasopharyngealcarcinoma risk with cytochrome P450 CYP1A1 gene polymor-phismsrdquo Chinese Journal of Preventive Medicine vol 43 no 7pp 586ndash590 2009

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[82] L R Bailey N Roodi C S Verrier C J Yee W D Dupontand F F Parl ldquoBreast cancer and CYPIA1 GSTM1 and GSTT1polymorphisms evidence of a lack of association in Caucasiansand African Americansrdquo Cancer Research vol 58 no 1 pp 65ndash70 1998

[83] E Taioli H L Bradlow S V Garbers et al ldquoRole of estradiolmetabolism and CYP1A1 polymorphisms in breast cancer riskrdquoCancer Detection and Prevention vol 23 no 3 pp 232ndash2371999

[84] V M Basham P D P Pharoah C S Healey et al ldquoPolymor-phisms in CYP1A1 and smoking no association with breastcancer riskrdquo Carcinogenesis vol 22 no 11 pp 1797ndash1800 2001

[85] N M Cury A Russo A L S Galbiatti et al ldquoPolymorphismsof the CYP1A1 and CYP2E1 genes in head and neck squamouscell carcinoma riskrdquoMolecular Biology Reports vol 39 no 2 pp1055ndash1063 2012

[86] LVarela-Lema E Taioli A Ruano-Ravina et al ldquoMeta-analysisand pooled analysis ofGSTM1 andCYP1A1 polymorphisms andoral and pharyngeal cancers a HuGE-GSEC reviewrdquoGenetics inMedicine vol 10 no 6 pp 369ndash384 2008

[87] N Masood F A Malik and M A Kayani ldquoExpression ofxenobiotic metabolizing genes in head and neck cancer tissuesrdquoAsian Pacific Journal of Cancer Prevention vol 12 no 2 pp 377ndash382 2011

[88] R Sharma M Ahuja N K Panda and M Khullar ldquoInterac-tions among genetic variants in tobaccometabolizing genes andsmoking are associatedwith head and neck cancer susceptibilityin north Indiansrdquo DNA and Cell Biology vol 30 no 8 pp 611ndash616 2011

[89] R Sharma N K Panda and M Khullar ldquoHypermethylation ofcarcinogen metabolism genes CYP1A1 CYP2A13 and GSTM1genes in head and neck cancerrdquo Oral Diseases vol 16 no 7 pp668ndash673 2010

[90] S S Sam V Thomas K S Reddy G Surianarayanan and AChandrasekaran ldquoGene-gene interactions of drugmetabolizingenzymes and transporter protein in the risk of upper aerodiges-tive tract cancers among Indiansrdquo Cancer Epidemiology vol 34no 5 pp 626ndash633 2010

[91] C Vaury R Laine P Noguiez et al ldquoHuman glutathioneS-transferase M1 null genotype is associated with a highinducibility of cytochromeP450 1A1 gene transcriptionrdquoCancerResearch vol 55 no 23 pp 5520ndash5523 1995

[92] T R Sutter Y M Tang C L Hayes et al ldquoComplete cDNAsequence of a human dioxin-inducible mRNA identifies a newgene subfamily of cytochrome P450 that maps to chromosome2rdquo Journal of Biological Chemistry vol 269 no 18 pp 13092ndash13099 1994

[93] Y M Tang Y Y P Wo J Stewart et al ldquoIsolation andcharacterization of the human cytochrome p450 CYP1B1 generdquoJournal of Biological Chemistry vol 271 no 45 pp 28324ndash28330 1996

[94] G I Murray W T Melvin W F Greenlee and M DBurke ldquoRegulation function and tissue-specific expression ofcytochrome P450 CYP1B1rdquo Annual Review of Pharmacologyand Toxicology vol 41 pp 297ndash316 2001

[95] XWen and TWalle ldquoCytochrome P450 1B1 a novel chemopre-ventive target for benzo[a]pyrene-initiated human esophagealcancerrdquo Cancer Letters vol 246 no 1-2 pp 109ndash114 2007

[96] M C E McFadyen S Breeman S Payne et al ldquoImmuno-histochemical localization of cytochrome P450 CYP1B1 inbreast cancer with monoclonal antibodies specific for CYP1B1rdquoJournal of Histochemistry and Cytochemistry vol 47 no 11 pp1457ndash1464 1999

[97] T M Sissung D K Price A Sparreboom and W D FiggldquoPharmacogenetics and regulation of human cytochrome P4501B1 implications in hormone-mediated tumor metabolism anda novel target for therapeutic interventionrdquo Molecular CancerResearch vol 4 no 3 pp 135ndash150 2006

[98] S Bandiera S Weidlich V Harth P Broede Y Ko andT Friedberg ldquoProteasomal degradation of human CYP1B1effect of the Asn453Ser polymorphism on the post-translationalregulation of CYP1B1 expressionrdquoMolecular Pharmacology vol67 no 2 pp 435ndash443 2005

[99] T Sliwinski P Sitarek T Stetkiewicz A Sobczuk and J BlasiakldquoPolymorphism of the ER120572 and CYP1B1 genes in endometrialcancer in a Polish subpopulationrdquo Journal of Obstetrics andGynaecology Research vol 36 no 2 pp 311ndash317 2010

[100] I Stoilov A N Akarsu I Alozie et al ldquoSequence analysisand homology modeling suggest that primary congenital glau-coma on 2p21 results from mutations disrupting either thehinge region or the conserved core structures of cytochromeP4501B1rdquo American Journal of Human Genetics vol 62 no 3pp 573ndash584 1998

[101] EAklilluMOscarsonMHidestrand B Leidvik COtter andM Ingelman-Sundberg ldquoFunctional analysis of six differentpolymorphic CYP1B1 enzyme variants found in an ethiopianpopulationrdquo Molecular Pharmacology vol 61 no 3 pp 586ndash594 2002

[102] P H Roos and H M Bolt ldquoCytochrome P450 interactionsin human cancers new aspects considering CYP1B1rdquo ExpertOpinion on Drug Metabolism and Toxicology vol 1 no 2 pp187ndash202 2005

[103] T Shimada J Watanabe K Inoue F P Guengerich and EM J Gillam ldquoSpecificity of 17120573-oestradiol and benzo[a]pyreneoxidation by polymorphic human cytochrome P4501B1 variantssubstituted at residues 48 119 and 432rdquo Xenobiotica vol 31 no3 pp 163ndash176 2001

[104] J S Mammen G S Pittman Y Li et al ldquoSingle aminoacid mutations but not common polymorphisms decreasethe activity of CYP1B1 against (-)benzo[a]pyrene-7R-trans-78-dihydrodiolrdquo Carcinogenesis vol 24 no 7 pp 1247ndash1255 2003

[105] R Thier T Bruning P H Roos and H M Bolt ldquoCytochromep450 1b1 a new keystone in gene-environment interactionsrelated to human head and neck cancerrdquoArchives of Toxicologyvol 76 no 5-6 pp 249ndash256 2002

[106] G Li Z Liu E M Sturgis R M Chamberlain M RSpitz and Q Wei ldquoCYP2E1 G1532C NQO1 Pro187Ser andCYP1B1 Val432Leu polymorphisms are not associated with riskof squamous cell carcinoma of the head and neckrdquo CancerEpidemiology Biomarkers and Prevention vol 14 no 4 pp1034ndash1036 2005

[107] M Sasaki Y Tanaka M Kaneuchi N Sakuragi and R DahiyaldquoAlleles of polymorphic sites that correspond to hyperactivevariants of CYP1B1 protein are significantly less frequent inJapanese as compared to American and German populationsrdquoHuman Mutation vol 21 no 6 p 652 2003

[108] C J Hopfer M C Stallings and J K Hewitt ldquoCommon geneticand environmental vulnerability for alcohol and tobacco use ina volunteer sample of older female twinsrdquo Journal of Studies onAlcohol vol 62 no 6 pp 717ndash723 2001


[109] IARC ldquoAlcohol drinking Biological data relevant to the evalu-ation of carcinogenic risk to humansrdquo IARCMonographs on theEvaluation of Carcinogenic Risks to Humans vol 44 pp 101ndash1521988

[110] A J Wight and G R Ogden ldquoPossible mechanisms by whichalcohol may influence the development of oral cancermdashareviewrdquo Oral Oncology vol 34 no 6 pp 441ndash447 1998

[111] V A Kobliakov A V Vaiman L N Pylev and L A VasilrsquoevaldquoExpression of mRNA for several enzymes of xenobiotic detox-ification in normal and spontaneously transformedmesothelialcells and mesothelioma cells of ratsrdquo Bulletin of ExperimentalBiology and Medicine vol 141 no 3 pp 353ndash356 2006

[112] Y L Cheung A C Kerr M C E McFadyen W T Melvinand G I Murray ldquoDifferential expression of CYP1A1 CYP1A2CYP1B1 in human kidney tumoursrdquo Cancer Letters vol 139 no2 pp 199ndash205 1999

[113] V Muthusamy S Duraisamy C M Bradbury et al ldquoEpigeneticsilencing of novel tumor suppressors in malignant melanomardquoCancer Research vol 66 no 23 pp 11187ndash11193 2006

[114] T Tokizane H Shiina M Igawa et al ldquoCytochrome P450 1B1is overexpressed and regulated by hypomethylation in prostatecancerrdquo Clinical Cancer Research vol 11 no 16 pp 5793ndash58012005

[115] G I Murray M C Taylor M C E McFadyen et al ldquoTumor-specific expression of cytochrome P450 CYP1B1rdquo CancerResearch vol 57 no 14 pp 3026ndash3031 1997

[116] C R M Rieder D B Ramsden and A C WilliamsldquoCytochrome P450 1B1 mRNA in the human central nervoussystemrdquo Journal of Clinical Pathology vol 51 no 3 pp 138ndash1421998

[117] J L Schwartz S Panda C Beam L E Bach and G RAdami ldquoRNA from brush oral cytology to measure squamouscell carcinoma gene expressionrdquo Journal of Oral Pathology andMedicine vol 37 no 2 pp 70ndash77 2008

[118] A Kolokythas J L Schwartz K B Pytynia et al ldquoAnalysis ofRNA from brush cytology detects changes in B2M CYP1B1 andKRT17 levels with OSCC in tobacco usersrdquo Oral Oncology vol47 no 6 pp 532ndash536 2011

[119] S Pradhan M N Nagashri K S Gopinath and A KumarldquoExpression profiling of CYP1B1 in Oral Squamous cell Carci-noma counterintuitive downregulation in tumorsrdquo PLoS ONEvol 6 no 11 Article ID e27914 2011

[120] E G Shatalova A J P Klein-Szanto K Devarajan E Cukier-man and M L Clapper ldquoEstrogen and cytochrome P4501B1 contribute to both early- and late-stage head and neckcarcinogenesisrdquo Cancer Prevention Research vol 4 no 1 pp107ndash115 2011

[121] J O Boyle Z H Gumus A Kacker et al ldquoEffects of cigarettesmoke on the human oral mucosal transcriptomerdquo CancerPrevention Research vol 3 no 3 pp 266ndash278 2010

[122] P G Sacks Z L Zhao W Kosinska K E Fleisher T Gor-don and J B Guttenplan ldquoConcentration dependent effectsof tobacco particulates from different types of cigarettes onexpression of drug metabolizing proteins and benzo(a)pyrenemetabolism in primary normal human oral epithelial cellsrdquoFood and Chemical Toxicology vol 49 no 9 pp 2348ndash23552011

[123] H K Kroemer and M Eichelbaum ldquoldquoItrsquos the genes stupidrdquoMolecular bases and clinical consequences of geneticcytochrome P450 2D6 polymorphismrdquo Life Sciences vol56 no 26 pp 2285ndash2298 1995

[124] C Sachse J Brockmoller S Bauer and I Roots ldquoCytochromeP450 2D6 variants in a Caucasian population allele frequenciesand phenotypic consequencesrdquo American Journal of HumanGenetics vol 60 no 2 pp 284ndash295 1997

[125] W L West E M Knight S Pradhan and T S Hinds ldquoInter-patient variability genetic predisposition and other geneticfactorsrdquo Journal of Clinical Pharmacology vol 37 no 7 pp 635ndash648 1997

[126] S Cholerton A Arpanahi N McCracken et al ldquoPoormetabolisers of nicotine and CYP2D6 polymorphismrdquo Lancetvol 343 no 8888 pp 62ndash63 1994

[127] M J deGroot andN P E Vermeulen ldquoModeling the active sitesof cytochrome P450s and glutathione S-transferases two of themost important biotransformation enzymesrdquo Drug MetabolismReviews vol 29 no 3 pp 747ndash799 1997

[128] M H Heim and U A Meyer ldquoEvolution of a highly poly-morphic human cytochrome P450 gene cluster CYP2D6rdquoGenomics vol 14 no 1 pp 49ndash58 1992

[129] M Garcia-Barcelo L W Chow H F K Chiu et al ldquoGeneticanalysis of the CYP2D6 locus in a Hong Kong Chinese popula-tionrdquo Clinical Chemistry vol 46 no 11 pp 18ndash23 2000

[130] L Ji S Pan J Marti-Jaun E Hanseler K Rentsch andM Hersberger ldquoSingle-step assays to analyze CYP2D6 genepolymorphisms in asians allele frequencies and a novel lowast14Ballele in mainland Chineserdquo Clinical Chemistry vol 48 no 7pp 983ndash988 2002

[131] A Gaedigk A Bhathena L Ndjountche et al ldquoIdentifica-tion and characterization of novel sequence variations in thecytochrome P4502D6 (CYP2D6) gene in African AmericansrdquoPharmacogenomics Journal vol 5 no 3 pp 173ndash182 2005

[132] L Bertilsson M L Dahl P Dalen and A Al-Shurbaji ldquoMolec-ular genetics of CYP2D6 clinical relevance with focus onpsychotropic drugsrdquo British Journal of Clinical Pharmacologyvol 53 no 2 pp 111ndash122 2002

[133] M V Gonzalez V Alvarez M F Pello M J MenendezC Suarez and E Coto ldquoGenetic polymorphism of N-acetyltransferase-2 glutathione S-transferase-M1 andcytochromes P450IIE1 and P450IID6 in the susceptibilityto head and neck cancerrdquo Journal of Clinical Pathology vol 51no 4 pp 294ndash298 1998

[134] C Matthias V Jahnke PW Jones et al ldquoCyclin D1 glutathioneS-transferase and cytochrome P450 genotypes and outcome inpatients with upper aerodigestive tract cancers assessment ofthe importance of individual genes using multivariate analysisrdquoCancer Epidemiology Biomarkers and Prevention vol 8 no 9pp 815ndash823 1999

[135] S S Yadav M Ruwali M C Pant P Shukla R L Singh andD Parmar ldquoInteraction of drug metabolizing cytochrome P4502D6 poor metabolizers with cytochrome P450 2C9 and 2C19genotypes modify the susceptibility to head and neck cancerand treatment responserdquo Mutation Research vol 684 no 1-2pp 49ndash55 2010

[136] J A G Agundez L Gallardo M C Ledesma et al ldquoFunction-ally active duplications of the CYP2D6 gene are more prevalentamong larynx and lung cancer patientsrdquoOncology vol 61 no 1pp 59ndash63 2001

[137] H Li L Feng Y Xu et al ldquoThe association of CYP2D6lowast10polymorphism with breast cancer risk and clinico-pathologiccharacteristics in Chinese womenrdquoActa Oncologica vol 45 no5 pp 597ndash601 2006

[138] L Laforest H Wikman S Benhamou et al ldquoCYP2D6 genepolymorphism inCaucasian smokers lung cancer susceptibility


and phenotype-genotype relationshipsrdquo European Journal ofCancer vol 36 no 14 pp 1825ndash1832 2000

[139] S Ouerhani R Marrakchi R Bouhaha et al ldquoThe role ofCYP2D6lowast4 variant in bladder cancer susceptibility in Tunisianpatientsrdquo Bulletin du Cancer vol 95 no 2 pp E1ndashE4 2008

[140] S Kato E D Bowman AM Harrington B Blomeke and P GShields ldquoHuman lung carcinogen-DNA adduct levels mediatedby genetic polymorphisms in vivordquo Journal of the NationalCancer Institute vol 87 no 12 pp 902ndash907 1995

[141] N E Caporaso C Lerman J Audrain et al ldquoNicotine meta-bolism and CYP2D6 phenotype in smokersrdquoCancer Epidemiol-ogy Biomarkers and Prevention vol 10 no 3 pp 261ndash263 2001

[142] S Hayashi J Watanabe and K Kawajiri ldquoGenetic poly-morphisms in the 5N-flanking region change transcriptionalregulation of the human cytochrome P450IIE1 generdquo Journal ofBiochemistry vol 110 no 4 pp 559ndash565 1991

[143] DW Nebert ldquoPharmacogenomics ethnicity and susceptibilitygenesrdquo Pharmacogenomics Journal vol 1 no 1 pp 19ndash22 2001

[144] Y C Chen and D J Hunter ldquoMolecular epidemiology ofcancerrdquo CA A Cancer Journal for Clinicians vol 55 no 1 pp45ndash54 2005

[145] F M Farin L G Bigler D Oda J K McDougall and CJ Omiecinski ldquoExpression of cytochrome P450 and micro-somal epoxide hydrolase in cervical and oral epithelial cellsimmortalized by human papillomavirus type 16 E6E7 genesrdquoCarcinogenesis vol 16 no 6 pp 1391ndash1401 1995

[146] S Liu J Y Park S P Schantz J C Stern and P LazarusldquoElucidation of CYP2E1 51015840 regulatory RsaIPstl allelic variantsand their role in risk for oral cancerrdquo Oral Oncology vol 37 no5 pp 437ndash445 2001

[147] M Ruwali A J Khan P P Shah A P Singh M C Pant andD Parmar ldquoCytochrome P450 2E1 and head and neck cancerinteraction with genetic and environmental risk factorsrdquo Envi-ronmental and Molecular Mutagenesis vol 50 no 6 pp 473ndash482 2009

[148] J Watanabe S Hayashi and K Kawajiri ldquoDifferent regulationand expression of the humanCYP2E1 gene due to the RsaI poly-morphism in the 5N-flanking regionrdquo Journal of Biochemistryvol 116 no 2 pp 321ndash326 1994

[149] K Tang Y Li Z Zhang et al ldquoThe PstIRsaI and DraIpolymorphisms of CYP2E1 and head and neck cancer risk ameta-analysis based on 21 case-control studiesrdquo BMC Cancervol 10 article 575 2010

[150] P Zhan J Wang Y Zhang et al ldquoCYP2E1 Rsa IPst I polymor-phism is associated with lung cancer risk among Asiansrdquo LungCancer vol 69 no 1 pp 19ndash25 2010

[151] I N Nishimoto T Hanaoka H Sugimura et al ldquoCytochromeP450 2E1 polymorphism in gastric cancer in Brazil case- con-trol studies of Japanese Brazilians and non-Japanese BraziliansrdquoCancer Epidemiology Biomarkers and Prevention vol 9 no 7pp 675ndash680 2000

[152] J Feng X Pan J Yu et al ldquoFunctional PstIRsaI polymorphismin CYP2E1 is associated with the development progression andpoor outcome of gastric cancerrdquo PLoS One vol 7 no 9 ArticleID e44478 2012

[153] S M N Garcia O A Curioni M B de Carvalho and G J FGattas ldquoPolymorphisms in alcohol metabolizing genes and therisk of head and neck cancer in a Brazilian populationrdquo Alcoholand Alcoholism vol 45 no 1 pp 6ndash12 2010

[154] L Balaji K B Singh and L V K S Bhaskar ldquoGeneticpolymorphisms of the CYP2E1 gene do not contribute to oral

cancer susceptibility in south Indiansrdquo Asian Pacific Journal ofCancer Prevention vol 12 no 6 pp 1523ndash1527 2011

[155] D Li C Dandara andM I Parker ldquoAssociation of cytochromeP450 2E1 genetic polymorphismswith squamous cell carcinomaof the oesophagusrdquoClinical Chemistry andLaboratoryMedicinevol 43 no 4 pp 370ndash375 2005

[156] T Ho Q Wei and E M Sturgis ldquoEpidemiology of carcinogenmetabolism genes and risk of squamous cell carcinoma of thehead and neckrdquoHead and Neck vol 29 no 7 pp 682ndash699 2007

[157] I Persson I Johansson H Bergling et al ldquoGenetic poly-morphism of cytochrome P4502E1 in a Swedish populationRelationship to incidence of lung cancerrdquo FEBS Letters vol 319no 3 pp 207ndash211 1993

[158] W D Leng X T Zeng Y J Chen et al ldquoCytochrome P4502E1 RsaIPstI polymorphism and risk of esophageal cancera meta-analysis of 17 case-control studiesrdquo Experimental andTherapeutic Medicine vol 4 no 5 pp 938ndash948 2012

[159] T Neuhaus Y D Ko K Lorenzen et al ldquoAssociation ofcytochrome P450 2E1 polymorphisms and head and necksquamous cell cancerrdquoToxicology Letters vol 151 no 1 pp 273ndash282 2004

[160] L K Guo C Zhang and X Guo ldquoAssociation of geneticpolymorphisms of aldehyde dehydrogenase-2 and cytochromeP450 2E1-RsaI and Alcohol consumption with oral squamouscell carcinomardquo Acta Academiae Medicinae Sinicae vol 34 no4 pp 390ndash395 2012

[161] A Rossini S Soares Lima D C M Rapozo M Faria RM Albano and L F Ribeiro Pinto ldquoCYP2A6 and CYP2E1polymorphisms in a Brazilian population living in Rio deJaneirordquo Brazilian Journal of Medical and Biological Researchvol 39 no 2 pp 195ndash201 2006

[162] F C Parra R C Amado J R Lambertucci J Rocha C MAntunes and S D J Pena ldquoColor and genomic ancestry inBraziliansrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 100 no 1 pp 177ndash182 2003

[163] J R Pimenta L W Zuccherato A A Debes et al ldquoColorand genomic ancestry in Brazilians a study with forensicmicrosatellitesrdquo Human Heredity vol 62 no 4 pp 190ndash1952006

[164] D Lu X Yu and Y Du ldquoMeta-analyses of the effect ofcytochrome P450 2E1 gene polymorphism on the risk of headand neck cancerrdquo Molecular Biology Reports vol 38 no 4 pp2409ndash2416 2011

[165] R Liu L H Yin andY P Pu ldquoAssociation of combinedCYP2E1gene polymorphism with the risk for esophageal squamouscell carcinoma in Huairsquoan population Chinardquo Chinese MedicalJournal vol 120 no 20 pp 1797ndash1802 2007

[166] E A Stephens J A Taylor N Kaplan et al ldquoEthnic variationin the CYP2E1 gene polymorphism analysis of 695 African-Americans European-Americans and Taiwaneserdquo Pharmacoge-netics vol 4 no 4 pp 185ndash192 1994

[167] J Wang Y Deng L Li et al ldquoAssociation of GSTM1 CYP1A1and CYP2E1 genetic polymorphism with susceptibility to lungadenocarcinoma a case-control study in Chinese populationrdquoCancer Science vol 94 no 5 pp 448ndash452 2003

[168] H C Hung J Chuang Y C Chien et al ldquoGenetic polymor-phisms of CYP2E1 GSTM1 and GSTT1 environmental factorsand risk of oral cancerrdquo Cancer Epidemiology Biomarkers andPrevention vol 6 no 11 pp 901ndash905 1997

[169] A Hildesheim L M Anderson C J Chen et al ldquoCYP2E1genetic polymorphisms and risk of nasopharyngeal carcinoma


in taiwanrdquo Journal of the National Cancer Institute vol 89 no16 pp 1207ndash1212 1997

[170] W H Jia Q H Pan H D Qin et al ldquoA case-controland a family-based association study revealing an associationbetween CYP2E1 polymorphisms and nasopharyngeal carci-noma risk in Cantoneserdquo Carcinogenesis vol 30 no 12 pp2031ndash2036 2009

[171] M Tsutsumi A Takada and J S Wang ldquoGenetic polymor-phisms of cytochrome P4502E1 related to the development ofalcoholic liver diseaserdquo Gastroenterology vol 107 no 5 pp1430ndash1435 1994

[172] S S Soya T Vinod K S Reddy S Gopalakrishnan andC Adithan ldquoCYP2E1 polymorphisms and gene-environmentinteraction in thw risk of upper aerodigestive tract cancersamong Indiansrdquo Pharmacogenomics vol 9 no 5 pp 551ndash5602008

[173] X Marichalar-Mendia M J Rodriguez-Tojo A Acha-SagredoN Rey-Barja and J M Aguirre-Urizar ldquoOral cancer andpolymorphism of ethanol metabolising genesrdquo Oral Oncologyvol 46 no 1 pp 9ndash13 2010

[174] Y Lu and A I Cederbaum ldquoCYP2E1 and oxidative liver injuryby alcoholrdquo Free Radical Biology andMedicine vol 44 no 5 pp723ndash738 2008

[175] A Butura K Nilsson K Morgan et al ldquoThe impact of CYP2E1on the development of alcoholic liver disease as studied in atransgenic mouse modelrdquo Journal of Hepatology vol 50 no 3pp 572ndash583 2009

[176] E Sim N Lack C J Wang et al ldquoArylamine N-acetyltransferases structural and functional implicationsof polymorphismsrdquo Toxicology vol 254 no 3 pp 170ndash1832008

[177] E Sim K Walters and S Boukouvala ldquoArylamine N-acetyl-transferases from structure to functionrdquo Drug MetabolismReviews vol 40 no 3 pp 479ndash510 2008

[178] H Wu L Dombrovsky W Tempel et al ldquoStructural basisof substrate-binding specificity of human arylamine N-acetyl-transferasesrdquo Journal of Biological Chemistry vol 282 no 41 pp30189ndash30197 2007

[179] M A Payton and E Sim ldquoGenotyping human arylamine N-acetyltransferase type 1 (NAT1) The identification of two novelallelic variantsrdquo Biochemical Pharmacology vol 55 no 3 pp361ndash366 1998

[180] GHGoodfellow JMDupret andDMGrant ldquoIdentificationof amino acids imparting acceptor substrate selectivity tohuman arylamine acetyltransferases NAT1 and NAT2rdquo Bio-chemical Journal vol 348 no 1 pp 159ndash166 2000

[181] D W Layton K T Bogen M G Knize F T Hatch V MJohnson and J S Felton ldquoCancer risk of heterocyclic aminesin cooked foods an analysis and implications for researchrdquoCarcinogenesis vol 16 no 1 pp 39ndash52 1995

[182] J M Dupret and D M Grant ldquoSite-directed mutagenesis ofrecombinant human arylamine N-acetyltransferase expressedin Escherichia coli Evidence for direct involvement of Cys68 inthe catalyticmechanism of polymorphic humanNAT2rdquo Journalof Biological Chemistry vol 267 no 11 pp 7381ndash7385 1992

[183] D W Hein ldquoAcetylator genotype and arylamine-induced car-cinogenesisrdquo Biochimica et Biophysica Acta vol 948 no 1 pp37ndash66 1988

[184] D W Hein M A Doll T D Rustan and R J FergusonldquoMetabolic activation ofN-hydroxyarylamines andN-hydroxy-arylamides by 16 recombinant human NAT2 allozymes effects

of 7 specific NAT2 nucleic acid substitutionsrdquo Cancer Researchvol 55 no 16 pp 3531ndash3536 1995

[185] R F Minchin P T Reeves C H Teitel et al ldquoN- and O-acetylation of aromatic and heterocyclic amine carcinogensby human monomorphic and polymorphic acetyltransferasesexpressed in COS-1 cellsrdquo Biochemical and Biophysical ResearchCommunications vol 185 no 3 pp 839ndash844 1992

[186] DWHeinM A Doll T D Rustan et al ldquoMetabolic activationand deactivation of arylamine carcinogens by recombinanthuman NAT1 and polymorphic NAT2 acetyltransferasesrdquo Car-cinogenesis vol 14 no 8 pp 1633ndash1638 1993

[187] D W Hein T D Rustan R J Ferguson M A Doll andK Gray ldquoMetabolic activation of aromatic and heterocyclicN-hydroxyarylamines by wild-type and mutant recombinanthumanNAT1 and NAT2 acetyltransferasesrdquoArchives of Toxicol-ogy vol 68 no 2 pp 129ndash133 1994

[188] A Hirvonen ldquoPolymorphic NATs and cancer predispositionrdquoIARC Scientific Publications no 148 pp 251ndash270 1999

[189] D W Hein ldquoMolecular genetics and function of NAT1 andNAT2 role in aromatic amine metabolism and carcinogenesisrdquoMutation Research vol 506-507 pp 65ndash77 2002

[190] M Drozdz T Gierek A Jendryczko J Pilch and J PiekarskaldquoN-Acetyltransferase phenotype of patients with cancer of thelarynxrdquo Neoplasma vol 34 no 4 pp 481ndash484 1987

[191] S Demokan Y Suoglu M Gozeler D Demir and N DalayldquoN-acetyltransferase 1 and 2 gene sequence variants and risk ofhead and neck cancerrdquoMolecular Biology Reports vol 37 no 7pp 3217ndash3226 2010

[192] M Unal L Tamer YAkbas et al ldquoGenetic polymorphismofN-acetyltransferase 2 in the susceptibility to laryngeal squamouscell carcinomardquo Head and Neck vol 27 no 12 pp 1056ndash10602005

[193] K Bendjemana M Abdennebi S Gara et al ldquoGenetic poly-morphism of gluthation-S transferases and N-acetyl trans-ferases 2 and nasopharyngeal carcinoma the Tunisia experi-encerdquo Bulletin du Cancer vol 93 no 3 pp 297ndash302 2006

[194] S Gara M Abdennebi S Chatti S Touati A Ladgham andF Guemira ldquoAssociation of NAT2 gene substitution mutationT341C with increased risk for head and neck cancer in TunisiardquoActa Oncologica vol 46 no 6 pp 834ndash837 2007

[195] S Henning I Cascorbi B Munchow V Jahnke and I RootsldquoAssociation of arylamineN-acetyltransferasesNAT1 andNAT2genotypes to laryngeal cancer riskrdquoPharmacogenetics vol 9 no1 pp 103ndash111 1999

[196] S Garte L Gaspari A K Alexandrie et al ldquoMetabolic genepolymorphism frequencies in control populationsrdquo CancerEpidemiology Biomarkers and Prevention vol 10 no 12 pp1239ndash1248 2001

[197] M Chatzimichalis J Xenellis A Tzagaroulakis et al ldquoGSTT1GSTM1 GSTM3 and NAT2 polymorphisms in laryngeal squa-mous cell carcinoma in a Greek populationrdquo Journal of Laryn-gology and Otology vol 124 no 3 pp 318ndash323 2010

[198] S C Buch V Nazar-Stewart J L Weissfeld and M RomkesldquoCase-control study of oral and oropharyngeal cancer in whitesand genetic variation in eight metabolic enzymesrdquo Head andNeck vol 30 no 9 pp 1139ndash1147 2008

[199] T Katoh S Kaneko R Boissy M Watson K Ikemura andA B Douglas ldquoA pilot study testing the association betweenN-acetyltransferases 1 and 2 and risk of oral squamous cellcarcinoma in Japanese peoplerdquo Carcinogenesis vol 19 no 10pp 1803ndash1807 1998


[200] S Fronhoffs T Bruning E Ortiz-Pallardo et al ldquoReal-timePCR analysis of the N-acetyltransferase NAT1 allele lowast3 lowast4 0lowast11lowast14 andlowast17 polymorphism in squamous cell cancer of headand neckrdquo Carcinogenesis vol 22 no 9 pp 1405ndash1412 2001

[201] J D McKay M Hashibe R J Hung et al ldquoSequence variantsof NAT1 and NAT2 and other xenometabolic genes and risk oflung and aerodigestive tract cancers in Central Europerdquo CancerEpidemiology Biomarkers and Prevention vol 17 no 1 pp 141ndash147 2008

[202] J A G Agundez ldquoPolymorphisms of human N-acetyltran-sferases and cancer riskrdquo Current Drug Metabolism vol 9 no6 pp 520ndash531 2008

[203] H Wang L Liu P E Hanna and C R Wagner ldquoCatalyticmechanism of hamster arylamine N-acetyltransferase 2rdquo Bio-chemistry vol 44 no 33 pp 11295ndash11306 2005

[204] K Szyfter Z Szmeja W Szyfter et al ldquoMolecular and cellularalterations in tobacco smoke-associated larynx cancerrdquo Muta-tion Research vol 445 no 2 pp 259ndash274 1999

[205] L Jiao M A Doll D W Hein et al ldquoHaplotype of N-acetyltransferase 1 and 2 and risk of pancreatic cancerrdquo CancerEpidemiology Biomarkers and Prevention vol 16 no 11 pp2379ndash2386 2007



Table1Po

lymorph

icCY

PsP4

50andNAT

sand

metabolism

ofcarcinogensintheH

NC

Gene

Substrate

Reference

Functio

naleffect

Polymorph

ismrsnu

mber

Reference

CYP1A1

TCa(egbenzo[a]pyrene

dimethylbenz[a]anthracene)

6-nitro

chrysene

[33]

PhaseI

oxidativea

ndredu

ctive

CYP1A1lowast

2A(m

1)Trarr

Csubstitutionatnu

cleotide

6235

inthe31015840

noncod

ingregion

mdash

[35]

CYP1A1lowast

2B(m

2)Ararr

GIle

462V

alrs1048943

CYP1A1lowast

3(m

3)Trarr

Csubstitutionatnu

cleotide

5996

inthe31015840

noncod

ingregion

mdash

CYP1A1lowast

4(m

4)Crarr

ATh

r461As

nrs1799814

CYP1B1

TCa(egbenzo[a]pyrene)

[92]

PhaseI

oxidativea

ndredu

ctive

CYP1B1lowast

3Va

l432Leu

rs1056836

[101]

CYP1B1lowast

2Arg48Ser

rs1056827

CYP1B1lowast

2Ala119

Ser

rs10012

CYP1B1lowast

4As

n453Ser

rs1800

440

CYP2

D6

TCa(egnicotin

eand

nitro

samines)

[126]

PhaseI

oxidativea

ndredu

ctive

CYP2


deletio

natexon

52549delA)

rs35742686

[129]

CYP2

D6lowast4(G

1934A)

rs3892097

CYP2

D6lowast5(le

adingto

gene

deletio

n)mdash

CYP2


deletio

natexon

31707delT)

rs5030655

CYP2

E1TC

a(egnitro

samines)

Ethano

l[24143144]

PhaseI

oxidativea

ndredu

ctive

CYP2

E1lowast

5B(c2)

(PstI

restric

tion

positionminus1019)

mdash[14

2]CY

P2E1lowast

5A(c1)(RsaIrestrictio

npo

sitionminus1259)

mdashCY

P2E1lowast

6(alleleD)(DraIrestrictio

nintro

n6)

rs64

13432

[149]

NAT1NAT

2Arylamines

andheterocyclica

romatic

amines

[181184186187]Ph

aseIIb

iotransfo

rmation

NAT1lowast

10T

1088A

rs1057126

[188]

NAT1lowast

10C

1095A

rs15561

NAT2lowast

5BIle114

Thr

NAT2lowast

5BLys268A

rgrs1801280

rs1208

NAT2lowast

6AA

rg197G

lnrs1799930

a Tob

acco

carcinogensmdashund

efined












1 2 43 5 6 87 109 11 120

5

10

15

20

25

30

Odd

s rat

io

lowast2

Alowast2

A

lowast2

Alowast2

A

lowast2

Alowast2

A

lowast1

Alowast2

A

lowast2

Alowast2

Am2

m2

m2

m2

m2

m2

Msp

Ia

Msp

I T3801

C

lowast2

Clowast2

C3798

CC3798

CTm1

m1

w1

m1

lowast4

lowast4






































C C C C CH

H

H H

H H

HHH

H

HHOH

C CH

H

H H

OH

OH

OH

Ethanol

ADH

NAD+ NADH++ H+ NAD+

+ H2O

ALDH


NADPH++ H+

+ O2

Ethanediol

H2O

NADP++ H2O

OC

O

CYP2E1

NADH + H+






(not to scale)

Poly Al A2

1 2 3 4 5 6 7 8 ORF





GenomicDNA


(a)




Human NAT2 gene


(b)







minus5

lowast4

lowast4

lowast4

lowast4

lowast4

lowast5

B

lowast5

B

lowast6

A

lowast6

A

lowast4

lowast6

A

lowast10

lowast10

a

lowast10

b

1 2 3 4 5 6 7 8 9

0

5

10

15

20

25

30

35

40

Odd

s rat

io

lowast5

Blowast5

B












CYP1A1






Indian 205245m1m1 812 327ndash2130 0000002

[79]w1m1 196 114ndash338 00092m2m2 631 224ndash1869 0000015



CYP1B1Indian 150150


[21]




CYP2D6Indian 350350



CYP2E1




Chinese 755755

rs9418990d 295 168ndash517 00002



58173





Table 2 Continued



[93]lowast6 156 106ndash227 lt005


[93]lowast6 204 127ndash329 lt005

NAT1 Japanese 62122



NAT2




Spanish75200

lowast6A 030 010ndash089 lt0042[133]








4 Conclusion





Abbreviations




Acknowledgment


References







































































































































































































































1 2 43 5 6 87 109 11 120

5

10

15

20

25

30

Odd

s rat

io

lowast2

Alowast2

A

lowast2

Alowast2

A

lowast2

Alowast2

A

lowast1

Alowast2

A

lowast2

Alowast2

Am2

m2

m2

m2

m2

m2

Msp

Ia

Msp

I T3801

C

lowast2

Clowast2

C3798

CC3798

CTm1

m1

w1

m1

lowast4

lowast4






































C C C C CH

H

H H

H H

HHH

H

HHOH

C CH

H

H H

OH

OH

OH

Ethanol

ADH

NAD+ NADH++ H+ NAD+

+ H2O

ALDH


NADPH++ H+

+ O2

Ethanediol

H2O

NADP++ H2O

OC

O

CYP2E1

NADH + H+






(not to scale)

Poly Al A2

1 2 3 4 5 6 7 8 ORF





GenomicDNA


(a)




Human NAT2 gene


(b)







minus5

lowast4

lowast4

lowast4

lowast4

lowast4

lowast5

B

lowast5

B

lowast6

A

lowast6

A

lowast4

lowast6

A

lowast10

lowast10

a

lowast10

b

1 2 3 4 5 6 7 8 9

0

5

10

15

20

25

30

35

40

Odd

s rat

io

lowast5

Blowast5

B












CYP1A1






Indian 205245m1m1 812 327ndash2130 0000002

[79]w1m1 196 114ndash338 00092m2m2 631 224ndash1869 0000015



CYP1B1Indian 150150


[21]




CYP2D6Indian 350350



CYP2E1




Chinese 755755

rs9418990d 295 168ndash517 00002



58173





Table 2 Continued



[93]lowast6 156 106ndash227 lt005


[93]lowast6 204 127ndash329 lt005

NAT1 Japanese 62122



NAT2




Spanish75200

lowast6A 030 010ndash089 lt0042[133]








4 Conclusion





Abbreviations




Acknowledgment


References



























































































































































































































































C C C C CH

H

H H

H H

HHH

H

HHOH

C CH

H

H H

OH

OH

OH

Ethanol

ADH

NAD+ NADH++ H+ NAD+

+ H2O

ALDH


NADPH++ H+

+ O2

Ethanediol

H2O

NADP++ H2O

OC

O

CYP2E1

NADH + H+






(not to scale)

Poly Al A2

1 2 3 4 5 6 7 8 ORF





GenomicDNA


(a)




Human NAT2 gene


(b)







minus5

lowast4

lowast4

lowast4

lowast4

lowast4

lowast5

B

lowast5

B

lowast6

A

lowast6

A

lowast4

lowast6

A

lowast10

lowast10

a

lowast10

b

1 2 3 4 5 6 7 8 9

0

5

10

15

20

25

30

35

40

Odd

s rat

io

lowast5

Blowast5

B












CYP1A1






Indian 205245m1m1 812 327ndash2130 0000002

[79]w1m1 196 114ndash338 00092m2m2 631 224ndash1869 0000015



CYP1B1Indian 150150


[21]




CYP2D6Indian 350350



CYP2E1




Chinese 755755

rs9418990d 295 168ndash517 00002



58173





Table 2 Continued



[93]lowast6 156 106ndash227 lt005


[93]lowast6 204 127ndash329 lt005

NAT1 Japanese 62122



NAT2




Spanish75200

lowast6A 030 010ndash089 lt0042[133]








4 Conclusion





Abbreviations




Acknowledgment


References





























































































































































































































minus5

lowast4

lowast4

lowast4

lowast4

lowast4

lowast5

B

lowast5

B

lowast6

A

lowast6

A

lowast4

lowast6

A

lowast10

lowast10

a

lowast10

b

1 2 3 4 5 6 7 8 9

0

5

10

15

20

25

30

35

40

Odd

s rat

io

lowast5

Blowast5

B












CYP1A1






Indian 205245m1m1 812 327ndash2130 0000002

[79]w1m1 196 114ndash338 00092m2m2 631 224ndash1869 0000015



CYP1B1Indian 150150


[21]




CYP2D6Indian 350350



CYP2E1




Chinese 755755

rs9418990d 295 168ndash517 00002



58173





Table 2 Continued



[93]lowast6 156 106ndash227 lt005


[93]lowast6 204 127ndash329 lt005

NAT1 Japanese 62122



NAT2




Spanish75200

lowast6A 030 010ndash089 lt0042[133]








4 Conclusion





Abbreviations




Acknowledgment


References































































































































































































































CYP1A1






Indian 205245m1m1 812 327ndash2130 0000002

[79]w1m1 196 114ndash338 00092m2m2 631 224ndash1869 0000015



CYP1B1Indian 150150


[21]




CYP2D6Indian 350350



CYP2E1




Chinese 755755

rs9418990d 295 168ndash517 00002



58173





Table 2 Continued



[93]lowast6 156 106ndash227 lt005


[93]lowast6 204 127ndash329 lt005

NAT1 Japanese 62122



NAT2




Spanish75200

lowast6A 030 010ndash089 lt0042[133]








4 Conclusion





Abbreviations




Acknowledgment


References





























































































































































































































Table 2 Continued



[93]lowast6 156 106ndash227 lt005


[93]lowast6 204 127ndash329 lt005

NAT1 Japanese 62122



NAT2




Spanish75200

lowast6A 030 010ndash089 lt0042[133]








4 Conclusion





Abbreviations




Acknowledgment


References































































































































































































































Abbreviations




Acknowledgment


References




























































































































































































































polymorphisms in the human cytochrome p450 and arylamine n-acetyltransferase: susceptibility to head...

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