dietary fat and its relationship to large bowel cancer1 · high intake of dietary fiber of certain...

[CANCER RESEARCH 41, 3700-3705, September 1981)0008-5472/81/0041-0000$02.00

Dietary Fat and Its Relationship to Large Bowel Cancer1

BandaruS. ReddyNaylor Dana Institute for Disease Prevention, American Health Foundation, Valhalla, New York 10595

Abstract

Epidemiological data have provided clues to the etiologicalfactors involved in large bowel cancer development. High intake of dietary fat tends to promote colon carcinogenesis.Studies in metabolic epidemiology have shown that the highdietary fat affects the metabolic activity of gut bacteria as wellas the levels of secondary bile acids that may act as tumorpromoters for the colon. Animal model studies indicate thattotal dietary fat, rather than type of fat, exerts a promoting rolein colon carcinogenesis.

Introduction

Although the concept that diet and nutrition might influencecancer is not a new one (56), this relationship has receivedsurprisingly little detailed attention. During the 1930's, a number of laboratories were interested in the possible influenceexerted by nutritional factors on susceptibility to cancer, butthe question soon lost the interest of both scientific and laycommunities. Now, there is a growing recognition that dietaryfactors play a predominant role in the etiology of cancer inman.

Following up on the leads advanced by epidemiologists,experimentalistshave found that nutrition, in general, is relatedto the development of cancer in 3 ways. (a) Food additives orcontaminants may act as carcinogens, cocarcinogens, or both;(b) nutrient deficiencies may lead to biochemical alterationswhich promote neoplastic processes; and (c) changes in theintake of selected macronutrients (protein, fat, etc.) may produce metabolic biochemical abnormalities which increase therisk of cancer. Although the relationship of nutrition and canceris complex and sometimes perplexing to those who visualizecarcinogens in terms of a specific carcinogen, it is important tounderstand that the promotional phase of carcinogenesis playsa major role in the relationship between nutrition and thedevelopment of cancer in general and, in particular, fat andcancer.

This review presents a brief evaluation of the current statusof the relationship between fat and colon cancer in man and ofthe use of animal models to determine if the etiological factorsestablished for man can be modified in an experimental setting,and will question the inconsistencies.

Etiological Factors

Epidemiological studies, discussed elsewhere in this workshop (15), have provided clues as to the etiological factorsinvolved in the development of large bowel cancer (16, 58) andsuggest that diet, particularly as it relates to high intake of fat

I Presented at the Workshop on Fat and Cancer, December 1 0 to 1 2, 1979,

Bethesda, Md. Supported by USPHS Contracts CR95604 and CP85659, andGrants CAl 2376, CAl 7613, and 16382 through the National Large BowelCancer Project from the National Cancer Institute.

and beef, and lack of fiber in the diet may be among the mostimportant factors associated with colon cancer in man (2, 10,22, 59).

To explain the relationship between dietary fat and colorectalcancer, it has been hypothesized that (a) the amount of dietaryfat determines both the concentration of acid and neutral sterolsubstrates in the large bowel and also the composition of themicroflora acting on such substrates; and (b) the gut microflorametabolize acid and neutral sterols to carcinogens active in thelarge bowel (1 , 24).

Attention has been focused on the possible role of bacteriain altering the structure of colonic steroids, as well as on thepotential carcinogenic activity of certain steroids. Investigators(13, 14, 21 ,23, 28) have examined the potential carcinogenicactivity of certain bile acids because (a) of their overall structure similarity to carcinogenic PAH2; (b) they may be converted chemically to 3-methylcholanthrene; (C) full aromatization of the bile acid nucleus would yield a carcinogen metabolitebased on cyclopentaphenanthrene; (d) human gut flora havebeen shown to achieve partial aromatization of the sterol ringsystem; and (e) several bile acids induced sarcomas at the siteof injection in experimental animals. It may be noted that suchmicroflora-mediated reactions are unlikely to yield PAH frombile salts but are much more likely to yield products which actas colon tumor promoters or cocarcinogens rather than ascomplete carcinogens (51). Thus, a high-fat diet changes thecomposition of bile acids as well as modifies the activity of gutmicroflora which may in turn produce tumor-promoting substances from bile acids in the lumen of the colon (24, 51 , 52).High intake of dietary fiber of certain type not only leads to anincrease in stool bulk, thereby diluting carcinogens and promoters (10, 40), but also alters the metabolism of putativecompounds.

Thus, we are concerned with 2 aspects: the search forcarcinogens and the search for modifying and, in particular,enhancing factors. Utilizing metabolic techniques and mutagenicity tests, experiments in this area are now feasible to seewhether carcinogens affecting the colon can be isolated, identified, and quantitated.

Bile Acids in Colon Carcinogenesis

The role of bile acids in colon carcinogenesis has receivedsome support from experimental studies. Chomchai et al. (11)observed that the carcinogenic effect of azoxymethane in ratswas increased by surgically diverting bile to the middle of thesmall intestine, which also raised the fecal excretion of bilesalts.

The evidence of the importance of bile acids as colon tumorpromoters came from our studies (Refs. 37, 46, 48, 50; Table1). The development of adenomas significantly increased

2 The abbreviations used are: PAH, polycyclic aromatic hydrocarbons; i.r.,

intrarectal(ly); MNNG, methyl-N'-nitro-N-nltrosoguanidlne; MNU, methylnitrosourea; DMH, 1,2-dimethylhydrazine cholesterol expoxide, cholesterol-5a,6a-epoxide.

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Colon tumor incidence in germ-free and conventional rats treated withi.r.MNNGand/or bileacidsCA

(cholic acid). CDC (chenodeoxycholic acid), or LC (lithocholic acid)groupreceivedI.r. 20 mg of sodium salt of respective bile acid 3 times weekly for48weeks;

MNNG group received i.r. 2 mg of MNNG twice a week for 2weeksfollowedby vehIcle for 46 weeks; MNNG plus CA, MNNG plus LC, or MNNGplusCDC

group received l.r. MNNG for 2 weeks and bile acid thereafter for 16weeksNo.

of tumors/rat% of animals with Adenocar

Rat tumors Total cinomaAdenomaGerm-freeCA(1O)'

0 0 00CDC(1O)0 0 00LC(1O)0 0 00MNNG(22)

27 0.27 0.140.13MNNG+ CA (24) 50 0.63 0.290.34MNNG+ CDC (24) 54 1.08 0.29 0.79

MNNG+LC(24) 71b 1.04 0.330.71ConventionalCA(12)

0 0 00CDC(12)0 0 00LC(12)0 0 00MNNG

(30) 37 0.55 0.23 0.32MNNG + CA (30) 67b 0.87 0.24 0.63MNNG + CDC (30) 70b@ .23 0.27 0.96MNNG + LC (24) 83b@ .83 0.33 1.50

Fat and Colon Cancer

among those conventional rats initiated with limited amounts ofi.r. MNNG to give a definite low yield of colon cancer and giveni.r. lithocholic acid or taurodeoxycholic acid as promoterscompared to the group that was given only the carcinogen.Deoxycholic acid applied topically to the colon increasedMNNG-induced colon adenocarcinomas in germ-free rats. Thebile acids themselves did not produce any tumors. A recentreport (27) indicatesthat, althoughlithocholicacid is not mutagenic in the Ames Salmonella-microsomal system, there isan increase of comutagenic activity when it is included in theAmes assay with known carcinogens.

A recent study also indicates that the primary bile acids,cholic acid and chenodeoxycholic acid, also produced aMNNG-lnduced colon tumor promoting activity in rats (50).Cholic acid and chenodeoxycholic acid given i.r. to conventional rats are subjected to bacterial 7aâ€”dehydroxylationtodeoxycholic acid and lithocholic acid, respectively. Cohen eta!. (12) reported that cholic acid in the diet increased MNUinduced colon carcinogenesis in rats. Total fecal bile acids,particularly deoxycholic acid output, was higher in animals fedcholic acid than in controls. This increase in fecal deoxycholicacid was due to bacterial 7a-dehydroxylation of cholic acid inthe colonic contents. These studies demonstrate that thesesecondary bile acids have a promoting effect in colon carcinogenesis.

The mechanism of action of bile acids in colon carcinogenesis has not been elucidated. Bile acids have been shown toaffect cell kinetics in the intestinal epithelium, although thestructural specificity of this effect has not been examinedextensively (3, 39). In the intestine, the data do not permit thecritical distinction to be made between a direct effect of bileacids on cell division, and an indirect or physiological stimulussecondaryto increased cell loss from sloughing or damage (3).The cell renewal system is dynamic and may be influenced bychanges in a number of factors including the composition ofgut microflora(33) and bile acids in the intestine(34). Recently,Cohen et a!. (12) reported an enhanced colonic cell prolifera

Table 1

tion in rats fed cholic acid as well as in animals treated with i.r.MNU. This increased cell population involved in DNA synthesisby cholic acid feeding would favor the expression of damageat a far higher level than with the carcinogen MNU alone,bringing about not only a greater overall incidence of MNUinduced colon tumors but also an enhanced number of tumorsin rats fed cholic acid. Lipkin (29) demonstrated that, duringneoplastic transformation of colonic cells, a similar sequenceof changes leading to uncontrolled proliferative activity develops in colon cancer in humans and in DMH-induced coloncancer in rodents.

Irrespective of the mechanism by which bile acids enhancecell proliferation and/or decrease the generation time of proliferating cells, the phenomenon may have important implications for colon carcinogenesis. Obviously, further studies arewarranted on the mechanism of tumor-promoting activity ofvarious bile acids.

Cholesterol and its Metabolites in Colon Carcinogenesis

Cruse etal. (17) proposed that prolonged exposure of dietarycholesterol is cocarcinogenic for human colon cancer in that itfacilitatesthe development, growth, and spread ofthe disease,since dietary fats promote the action of several experimentalcarcinogens. Broitman et a!. (7) studied the effect of polyunsaturated fat and cholesterol on colon tumorigenesis and demonstrated that the interaction between dietary polyunsaturatedfat and dietary cholesterol and/or tissue cholesterol may promote tumorigenesis compared with dietary saturated fat andcholesterol in the animal model.

Bischoff(5) has reviewed the carcinogenic effects of steroidsand reported that cholesterol epoxide administered in anaqueous vehicle was carcinogenic in both rats and mice, butnot carcinogenic to the colon. Cholesterol-3@,5a,6fl-triol, aprincipal metabolite of cholesterol epoxide, has been found inincreased levels in feces of patients of colon cancer andulcerative colitis (43). Recently, Hwang and Kelsey (26) demonstrated in the human colon the presence of microbial epoxidehydrase activity which metabolizes cholesterol epoxide to triol.

The mutagenic as well as colon tumor-promoting activity ofcholesterol and its metabolites has been tested (54). Naturally,air-aged commercial samples of cholesterol contain components which are mutagenic towards Salmonella typhimuriumTA1537, TA1538, and TA98, but cholesterol epoxide is nonmutagenic towards these strains (54). We also found thischemical negative in an Ames assay. Our recent studies alsoindicate that cholesterol, cholesterol epoxide, and triol do notexhibit any colon tumor-promoting activity in both germ-freeand conventional rat models (48). These observations suggestthat these compounds or their metabolites, produced by thecolonic bacteria, are not detectably either carcinogenic orpromoter to the colonic mucosa.

Mutagens (or Presumptive Carcinogens) in the Colon

The question has often been raised whether the dietary andbody fat would act as a reservoir for environmental contaminants such as PAH, polychlorinated biphenyl, polybrominatedbiphenyl, dichlorodiphenyltrichloroethane, and the like. Noneof these contaminants have ever induced cancer in animalmodels in the colon.

An important clue as to the nature of carcinogens came froma Numbers in parentheses, number of rats.b SignIficantly dlfferentfrom rats given MNNG alone by x@test; p < 0.05.

SEPTEMBER1981 3701



Mutagenic activity of fecal samples collected from healthy male subjectsfromKuopio,Finland, and New York metropolitanarea%

of samples with mutagenic ratio>3aTA98

TA100 Mutagenlcactivityinat+

â€” + â€” TA98 & least onePopulation group S9 59 S9 59 TA1oob testsystemNew

York non-Seventh-Day 0 22 6 11 11 22Adventists(18fKuopio(15)

0 13 0 0 013NewYork Seventh-Day 0 0 0 0 00Adventists

(11)

B. S. Reddy

determine the relevance of these findings to colon cancer inman.

Metabolic Epidemiology

Investigations in man have also been carried out in severallaboratoriesto determine whether (a) changes in the diet wouldalter the concentration of fecal bile acids, cholesterol metabolites, and the activity of fecal microflora; and (b) differences infecal constituents occur between high-risk and low-risk populations for colon cancer.

Hill et al. (24) observed a correlation between the death ratedue to colon cancer, fecal anaerobes, and fecal excretion ofcholesterol and bile acid metabolites as well as their degradation by the gut flora. In addition, the feces from U. S. andEnglish subjects contained higher levels of nuclear dehydrogenerating Clostridia than subjects from African and Asiancountries (23). The implication is that nuclear dehydrogenerating Clostridia is involved in the production of unsaturatedsteroids from bile acid nucleus (23, 25). Neither Moore andHoldeman (35) nor Finegold and Sutter (19) have seen significant differences in the composition of fecal flora of high-riskand low-risk populations for colon cancer. Of primary importance in investigating the etiology of large bowel cancer is anunderstanding of the influence of dietary constituents on theenzyme (metabolic) activities of gut bacteria rather than identification of specific fecal bacteria. Various fecal bacterial enzymes such as f3-glucuronidase, 7a-dehydroxylase, cholesterol dehydrogenase, 7a-hydroxysteroid dehydrogenase, andnuclear dehydrogenase reflect not only the metabolic activityof the colonic bacteria but also functional capabilitiesof colonicbacteria to produce putative compounds in the gut.

Reddy and Wynder (52) investigated fecal microbial $-glucuronidase activity in the feces to assess the degree of microbial activity for the enzymic hydrolysis of various complexconjugates in the large bowel of various population groups(Americans on a high-fat, mixed Western diet; Seventh-DayAdventists on a mixed Western diet without meat and less fat;Japanese; Chinese-Americans consuming Chinese diet; andstrict vegetarians). The fecal bacteria of Americans consuminga high-fat, mixed Western diet had a higher $-glucuronidaseactivity than other groups. Studies comparing a high-fat, highmeat diet with a no-meat, low-fat diet showed that the formerresulted in elevated levels of fecal bacterial fl-glucuronidaseactivity. Macdonald et a!. (30) showed that the fecal NAD- andNADP-dependent 7a-hydroxysteroid dehydrogenase whichconverts hydroxy-bile salts to keto-bile salts was lower invegetarian Seventh-Day Adventists than in non-Seventh-DayAdventists consuming a mixed Western diet. We have extendedthese studies to other bacterial enzymes and found that ,8-glucuronidase, 7a-dehydroxylase, and 7a-HSDA were lower invegetarian Seventh-Day Adventists than in non-Seventh-DayAdventists in the New York Metropolitan area (Table 3). Thus,it becomes evident that a high-risk diet can alter the metabolicactivity of gut microflora and that this effect could play anactive role in the etiology of large bowel cancer.

The effect of dietary fat on fecal bile acid excretion has beenstudied in various laboratories and discussed elsewhere in thisworkshop by Reddy (40). In a recent study, comparison offecal bile acids was carried out between Seventh-Day Adventists who are lacto-ovo-vegetarians and non-Adventists con

the studies of Nagao etal. (36) who demonstratedthe presenceof mutagens (presumptive carcinogens) in the charred surfaceof beef and fish. They speculated that this activity was theresult of pyrolysis of the proteins and subsequently demonstrated mutagenicity of protein pyrolysates. Pyrolysis of mdividual amino acids was carried out, and the pyrolysate oftryptophan had the greatest mutagenic activity (32). The activeprinciple in this pyrolysate was a â€˜y-carbolinederivative, aheterocyclic o-methylarylamine (55). Other o-methylarylamines (i.e. , 3,2'-dimethyl-4-aminobiphenyl)have been shown toproduce colon cancer in male and female animals and breastcancer in female animals (47). In view of the rather well-established connection between mutagenic activity and carcinogenicactivity and the known properties of certain o-methylarylaminesespecially in causing colon cancer in rats, it is likely thatbroiling and frying of meat may lead to carcinogens responsiblefor cancer of the colon (57).

Recently, Bruce et al. (8) have reported the presence ofmutagenic substances in the stools of some individuals whichthey thought were N-nitroso compounds that might be responsible for colon cancer. It will be important to determine whetherthis mutagen stems from the metabolism of a mutagen fromfried meats or whether it is derived from other precursors, suchas through a nitroso exchange reaction (31) or an as yetunknown pathway, including a nitrosation at the pH prevailingin the large intestine.

Bruce et al. (8) have also demonstrated that increased dietary fiber and decreased dietary fat and protein reduced fecalmutagen levels. A marked diminution of mutagen concentrationcould also be brought about supplementing diets with eitherascorbic acid or a-tocopherol. In another study, the fecalexcretion of mutagens positive to S. typhimurium TA100 andTA98 without microsomal activation was higher in South African urban whites, who are at high risk for colon cancer, thanin South African urban and rural blacks, a low-risk populationfor colon cancer (18). Our recent studies indicate that theincidence of fecal mutagenic activity was higher in subjectsfrom New York consuming a high-fat, high-meat diet than inthe low-risk rural population of Kuopio, Finland, consuming ahigh-fat, high-fiber diet (Table 2). None of the vegetarian Seventh-Day Adventists consuming a low-fat diet showed anymutagenic activity. Mandel et a!. (31) have demonstrated thatthe stools of certain people contained a bacterial enzyme whichcould transfer a nitroso group from a nitrosamine to an amidewith consequent reduction of what is presumably a directacting nitrosamide. More research in this area is necessary to

Table 2

a Mutagenic ratio is the number of his@ revertant colonies on the test platedivided by the number of his@spontaneous revertant colonies on control plates.

b Samples showing activity both in TA98 and TA1 00 tester systems.C Numbers in parenthesis, number of samples tested.

CANCER RESEARCH VOL. 413702



% of diet fatCarcinogenLard525DM118172025DMH67Corn

oil525DMH362025DMH64Beef

fat2022DMHb60522DMH272022MNUc73522MNU332022MAM

acetateC@80522MAMacetate45

Bacterial enzymeSeventh-Da1Adventists

(22)bNon-SeventhDay Adventistsa

(40)fi@glucuronIdaseC

7a@dehydroxyI__@CCholesterol dehydrogenasecNADP-dependent 7a-hydroxysterold

dehydrogenaseÂ°4.2

Â± 0.5â€•36 Â± 838 Â±10

6.2 Â± 0.9i

2.8 Â± 1 fO'70 Â±1042 Â±1212.8 Â± 1.2@

Fecal bile acid pattern in vegetarian Seventh-DayAdventists andnon-Seventh-DayAdventistsPreliminaryresults of 20 healthy strict vegetarian Seventh-Day Adventists consuming a lacto-ovo

vegetarian diet for more than 10 years and 40 healthy non-Seventh-Day Adventists consuming a high-fat,high-meat diet. In Seventh-Day Adventists, 27% of total caloric intake was from fat, whereas in nonAdventists, 39% of total caloric intake was from fat. The fiber intake of Seventh-Day Adventists was about2.5-fold higher than in non-Adventists.mg/g

dry feces mg/dayNon-Seventh

Seventh-Day Ad- Non-Seventh-Day Seventh-Day Ad- Day AdventistsBile acids ventists(20) Adventlsts(40) ventists(20)(40)Cholic

0.1 Â±0,02a 0.2 Â±0.04 5 Â± 0.1 5 Â±0.9Chenodeoxycholic0.1 Â±0.03 0.2 Â±0.03 5 Â± 0b2@@ 0.8

Deoxycholic 1.3 Â±0.14@' 45 Â±0.3 66 Â± 9 113 Â± 8Lithocholic 1.0 Â±006b 4.0 Â±0.2 51 Â± 6b@ oo Â± 712-Ketolithochollc 0.04 Â±0,01b 0.4 Â±0.02 2 Â± 0.1b@ o Â± 0.3Ursodeoxycholic 0.04 Â±OOl@ 0.3 Â±0.04 2 Â± 0.1â€• 8 Â± 0.3Other 1.62Â±0.2 3.5Â±0.4 83Â± 8 88Â± 6Total 4.20 Â±0,2b 13.1 Â±0.6 214 Â±14b 329 Â±20


(40%) and high corn oil (20%) led to more DMH-induced colontumors in F344 rats than did control diets of beef protein (20%)and low beef fat (6%) or soybean protein (20%) and low-cornoil content (6%) (45).

Furthermore, F344 rats fed a diet containing 20% beef fatand treated i.p. with methylazoxymethanol acetate, s.c., withDMH, or i.r. with MNU had a greater incidence of colon tumors

than did rats fed a diet containing 5% beef fat and treatedsimilarly (Ref. 49; Table 5). W/Fu rats fed a 30% lard diet hada higher number of DMH-induced large bowel tumors thananimals fed the standard diet (4). Broitman et a!. (7) showedthat rats fed a 20% safflower oil diet had more DMH-inducedlarge bowel tumors than those animals fed either the 5% or20% coconut oil diets. However, these studies provide noevidence that dietary polyunsaturated fat per se is more effective than saturated fat in augmenting tumorigenesis by DMH.Rogers and Newberne (53) found that a diet marginally deficient in lipotropes but high in fat enhanced DMH-induced coloncarcinogenesis in Sprague-Dawley rats. In general, these re

Table 5Colon tumor incidence in rats fed-diets high in fat and treated with carcinogens

% of protein % of rats with(casein) colon tumors

suming a high-fat mixed Western diet (Table 4). The fecalexcretion of secondary bile acids, deoxycholic acid and lithocholic acid, was lower in Seventh-Day Adventists than in nonAdventists, and the fat intake was about 28% lower in SeventhDay Adventists.

Experimental Studies: Dietary Fat in Colon Carcinogenesis

Research on the mechanism of cancer causation in the largebowel has been assisted by the discovery over the last 20years of several chemicals which induce colon cancer in animalmodels that mirror the type of lesions seen in man (6). Nigro eta!. (38) Induced intestinal tumors in rats by azoxymethane andcompared animals fed a high-beef-fat diet and those on a lowfat diet. Animals fed a high-fat diet developed more intestinaltumors and with more metastasis than the rats fed a low-fatdiet. Inasmuch as humans in various populations usually followcomparable dietary regimens over generations, Reddy et al.(44) desIgned experiments in which animals were exposed toa given regimen for 2 generations prior to treatment with DMH.Animals fed 20% lard or 20% corn oil were more susceptibleto colon tumor induction by s.c. DMH than those fed 5% fat(Table 5). The type of fat appears to be immaterial at a 20%level, although at a 5% level, there is a suggestion that unsaturated fat (corn oil) predisposes to more DMH-induced colontumors than saturated fat (lard). Combinations of high beefprotein (40%) and high beef fat (20%) or high soybean protein

Table 3Fecalbecterialenzymes in Seventh-DayAdventists and non-Seventh-Day

Adventists

a Female F344 rats, at 7 weeks of age, were given DMH s.c. at a weekly dose

rate of 10 mg per kg body weight for 20 weeks and autopsied 10 weeks later.Male F344 rats, at 7 weeks of age, were given a single s.c. dose of DMH,

150 mg per kg body weight, and autopsied 30 weeks later.c Male F344 rats, at 7 weeks of age, were given MNU i.r., 2.5 mg/rat, twice

in one week and autopsied 30 weeks later.d Male F344 rats, at 7 weeks of age, were given a single i.p. dose of MAM

(methylazoxymethanol) acetate, 35 mg per kg body weight, and autopsied 30weeks later.

a@ Adventists are strict vegetarians from the New York metropolltan area. Non-Seventh-Day Adventists are on a high-fat, high-meat, mixedwegtern diet.

Numbersln parentheses, number of individuals tested.C Activity per mg dry feces.

M@ Â±SE.0 ActIvIty per mg protein.

f SignIficantly different from Seventh-Day Adventists.

Table 4

a Mean Â±SE.b Significantly different for non-Adventists; p < 0.01.

SEPTEMBER 1981 3703



B. S. Reddy

suIts suggest that the total dietary fat, rather than the type offat, may have a function in the pathogenesis of colon cancer.

The effect of high dietary fat on biliary and fecal bile acidpattern has been reviewed in this workshop (40). Biliary excretion of total bile acids as well as cholic acid, $-muricholic acid,ursodeoxycholic acid, and deoxycholic acid and fecal excretion of deoxycholic acid, lithocholic acid, and 12-ketolithocholic acid were higher in rats fed a diet containing 20% cornoil or 20% lard than in rats fed diets containing 5% corn oil or5% lard (41).

Recent studies indicate that the enhanced tumorigenesis inthe animals fed the high-fat diet is due to promotional effectsrather than alterations in carcinogen metabolism (9). Whilethere is no generalized theory of the mechanism of tumorpromotion of high dietary fat, the above results in animal modelsuggest that colon tumor promotion through a mechanisminvolving increased colonic bile acid content.

Experiments were conducted to delineate the effects ofvarious dietary factors on the metabolic activity of intestinalmicroflora in order to understand the relationship of coloncancer to diet-mediated changes in the intestinal bacteria.Goldin and Gorbach (20) reported that rats fed a meat diet hadhigher levels of fecal bacterial fl-glucuronidase, azoreductase,and nitroreductase activities than did grain-fed rats. After confirming these studies, Reddy et a!. (42) extended the observation that not only a meat diet but also a high-fat diet or highprotein, high-fat diet changes the bacterial /.@-gIucuronidaseactivity in the large intestine. Although it is premature to condude from these studies that factors altering microflora enzymes have an effect on tumor formation in the large bowel,these changes in metabolic activity of microflora might alter thebiological activity, toxicity, excretion, and reabsorption of manyof the endogenous and exogenous compounds such as carcinogen and/or cocarcinogen metabolites.

Conclusion

In recent years, salient advances have taken place in ourknowledge of factors in the etiology of large bowel cancer inman. Laboratory studies have shown the importance of theinteraction of high-fat diet and the production of bile acidspotentially relevant in the etiology of colon cancer. Animalmodel studies also indicate that total dietary fat, rather thantype of fat, plays a role in colon carcinogenesis. More interestin collateral areas such as physiology and biology of colon andassociated cell systems has provided the information that thebile acids in the gut enhance cell proliferation and/or decreasethe generating time of proliferating cells, the phenomenon ofwhich may have important implications for colon carcinogenesis.

Reports on the mechanisms of carcinogenesis have placedemphasis on carcinogens. Attempts have been made in variouslaboratories to isolate and identify the carcinogens affectingthe colon. Some investigators claim that broiling and/or fryingof meat and fish and the browning reactions between sugarsand amines yield mutagens (presumptive carcinogens) responsible for cancer of the colon. Others have reported the presence of mutagenic N-nitroso compounds in human feces thatmight be responsible for colon cancer.

Although many substances are tumorigenic in experimentalanimals and a lesser number are carcinogenic in man, signifi

cant modifying factors enhance the effect of low-dose or lowpotency carcinogens that by themselves would not suffice toinduce cancers. In some instances, the modifying factor canbe readily identified and removed, thereby eliminating or reducing the incidence of certain cancers. This is not usuallypossible with initiating carcinogens. In the case of colon cancer, evidence has been presented that dietary fat exerts apromoting effect on tumorigenesis. Therefore, rather than concentrating on specific carcinogens, more attention must begiven to modifying factors, i.e. , cocarcinogens, promoters, andfactors that influence the formation of endogenous tumorigeniccompounds.

It needs to be asked where do we go from here in terms offurther research. Needless to say, we need to continue and,indeed, to expand work in metabolic epidemiology and inlaboratory studies to pinpoint the specific agents related tocolon carcinogenesis.

References

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1981;41:3700-3705. Cancer Res Bandaru S. Reddy Dietary Fat and Its Relationship to Large Bowel Cancer

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