metabolism of foreign comounds - univerzita … of foreign...drug metabolism = xenobiochemistry...
TRANSCRIPT
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BIOCHEMISTRY
GENERAL MEDICINE
METABOLISM OF FOREIGNCOMPOUNDS
RNDr. Zdeněk DVOŘÁK, PhD.Department of Medical Chemistry and BiochemistryFaculty of Medicine, Palacky University Olomouc
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DRUG METABOLISM = XENOBIOCHEMISTRY
Foreign compounds = XENOBIOTICS (lipophilic molecules)= drugs, alkaloids, pesticides, toxic industrial chemicals etc.
BiologicalDefence ofOrganism
ANTIOXIDANT SYSTEM• protection against oxygen radicals,oxidants, ionizing radiation
DETOXICATION SYSTEM• protection against chemicals
DETOXICATION = consecutive increase of molecule polarity to enhance its exctretion= A.D.M.E. (absorption-distribution-metabolism-elimination)= biotransformation
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BIOTRANSFORMATION
Phase I.
• oxygenation• reduction• hydrolysis
Phase II.
• conjugation
Phase III.
• transport
Xenobioticdetoxication
activation
Hinderedoxygenation
Reactiveintermediates
GSH; proteinsSH-enzymes; DNA
Covalent bindingand toxicity(neoantigens,mutagens,carcinogenes)
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DRUG ACCUMULATION
TOXICITY
CYP1; CYP2CYP3; CYP4
Therapeuticeffects
OXIDIZED METABOLITES
PhysiologicalPathological
GeneticEnvironmental
FACTORS
CONJUGATIONENZYMES
PROTEINS DNA
Cell damage Mutation
TOXICITY
INACTIVATION
ELIMINATION
DETOXICATION
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BIOTRANSFORMATION: Phase I. („oxido-reductive“)
1. Oxygenation – hydroxylation (monooxygenases)
HR1
R3R2 OH
R1
R3R2
aliphatic
R1
R2
R1
R2
OH
aromatic
2. Oxidative demethylation (monooxygenases)
OMe OCH2OH OH
HH
O+
O-demethylation
CH2
NH
CH3RCH2
NH
CH2OHRCH2
NH2
RH
HO
+
N-demethylation
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BIOTRANSFORMATION: Phase I. („oxido-reductive“)
3. Oxidation – (dehydrogenases)
CH3 CH2
OH CH3
H
OCH3
OH
O
NAD+ NADH + H+ NAD+ NADH + H+
H2O
4. Reduction – (dehydrogenases; reductases)
R1
R2O
R1
R2
H
OH
R1
R2
NO2 R1
R2
NH2
NAD+NADH + H+
5. Hydrolysis – (hydrolases; esterases; amide hydrola ses)
R1O
O
R2
R1NH
O
R2
R1O
O
H
R1O
O
H
R2 OH
R2 NH2
+
+
H2O
H2O
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CYTOCHROME P-450: Ubiquitous monooxygenase
HEME PROTEIN - 1 protoporphyrin III. – Fe3+ coordinated to HS-Cys of apoenzyme- integral membrane protein (ER; outer mitochondria )
DETERMINATION – spectrophotometry of a complex with CO: Cyt P450-Fe2+-CO hastypical absorption at 450 nm
450 nmA
λλλλACTIVE SITE - 1. binding site for substrate
- 2. heme – binding and activation of O2
LOCALIZATION - LIVER (+ extrahepatic tissues – placenta; lungs; intestine etc.)- not present in serum, muscle, neurons, erythrocyte etc.
NUMBER - cca 150 enzymes (4 families); 17 representatives in man- classification according primary structure- present in man, animals, plants, fungi, bacteria
CYP1A1
cytochromeP450
family
Sub-family
individualenzyme
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CYTOCHROME P-450: Ubiquitous monooxygenase
DIFFERENCES - substrate and reaction specifity- tissue and cell localization- mode of regulation
REGULATION - transcriptional – induction of gene expression (CYP1, 2B, 2C, 3A)- posttranslational (CYP2E1)- polymorphism (CYP2D6) – rapid vs. slow metabolizers- inhibitors, substrates
INDUCTION - increased de novo synthesis of Cyt P-450 in response to exposureto inducers (substrates)- potent inducers are often slowly metabolized substrates- PAH, PCB, rifampicin, phenobarbital, carbamazepine, midazolam…
P450sinduction
ACCELERATED DETOXICATION/METABOLISM• decreased drug effects; loss of therapeutic effects• compensation – increased doses of the drug
INCREASED SYNTHESIS OF REACTIVE METABOLITES• carcinogenesis (PAH – smokers – lungs; PCB - placenta)• immune toxicity; oxygen radicals
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R-H + O-O + NADPH + H+ R-OH + H2O + NADP+
• cytochrome P450 mixed function oxidase (MFO)• microsomal drug-metabolizing system (MDMS)
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Cytochrome P450 subfamilies
CYP1 CYP2 CYP3 CYP4 CYP11 CYP17 CYP19 CYP21
1A1 2A6 3A3 4A9 11A1 21A21A2 2A7 3A4 4A11 11B1
2B6 3A5 4B1 11B22C8 3A7 4F22C9 4F32C102C182C192D62E1
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CYP Content Phenotypic substrates Inducers Inhibitors(pmol/mg) In vivo In vitro
CYP1A1 <0.5 ethoxyresorufin - TCDD, BNF, 3MC αααα-NF omeprazole,lansoprazole
CYP1A2 0.5-33.5 acetanilide caffeine TCDD, BNF, 3MC fura fyllinephenacetin omeprazole propranolol
lansoprazole fluvoxamineCYP2A6 45 coumarin coumarin phenobarbital, dithiocarbama te
dexamethasone pilocarpinerifampicin
CYP2B6 7 cyclophosphamide - phenobarbital orphenadrinerifampicin
CYP2C9 40-277 warfarin warfarin phenobarbital sulfaphena zolerifampicin
CYP2C19 - (S)-mephenytoin (S)-mephenytoin phenobarbital omeprazolerifampicin
CYP2D6 10 debrisoquine dextromethorphan - quinidineCYP2E1 <5-50 chlorzoxazone chlorzoxazone alcohols diethy ldithio-
organic solvents carbamateCYP3A4 81-360 cyclosporin A erythromycin rifampicin trole andomycin
nifedipine cortisol phenobarbital ketokonazoleomeprazole gestodenelansoprazoledexamethasoneothers.
Average content, phenotypic substrates, specific induc ers and inhibitors of human CYP enzymes
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BIOTRANSFORMATION: Phase II. („conjugation“)
METABOLITE (phase I.)(chemical)
+ CONJUGATINGREAGENT CONJUGATE
CONJUGATING REAGENT:• endogenous polar compound• product of cellular metabolism• glucuronic acid = glucuronidation• sulphuric acid = sulphatation• glutathione• amino acids = e.g. Hippuric acid• acetyl CoA = acetylation• S-adenosylmethionine = methylation
CONJUGATES:• higly polar, mostly ionized compounds• e.g. Glucuronide; suphate; mercaptouricacid;acylaminoacid; acetylderivative etc.• inactivation by exctretion(urine Mw<400; bile Mw > 400
ENERGY FOR CONJUGATION:• ATP (amino acid)• conjugating reagent – activated donor of conjugating grou p
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Conjugation with GLUCURONIC ACID
SUBSTRATES: alcohols; phenols; amines; thiols; carbo xylic acid
DONOR: UDP-GA = Uridine- DiPhospho- Glucuronic- Acid
O
OH
OH
OH
COOH
O P P O CH2
N
NH
O
OHOH
O
O
ENZYME: UDP-glucuronyl transferase
PRODUCTS: O-glucuronidesN-glucuronides
R OH
R NH2
+ UDP-GA UDP+
R NH GA
R O GA
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Conjugation with SULPHURIC ACID
SUBSTRATES: alcohols; phenols; arylamines
DONOR: PAPS = 3-Phospo Adenosine-5´- Phospho Sulphate
ENZYME: sulphotransferases; cytosolic
PRODUCTS: sulphates
R OH + PAPS PAP(phosphoadenosinephosphate)+R O SO3
OPOSO3
N
N
N
N
NH2
O
O OH
P
CH2
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Conjugation with GLUTATHIONE
SUBSTRATES: aromatic hydrocarbons and heterocycles; hal ogen derivatives;epoxides; etc.
DONOR: GSH = γγγγ-glutamyl-cysteinyl-glycine; tripeptide
ENZYMES: 1. GSH-S-transferases; cytosolic; conjugate remains in cell2. γγγγ-glutamyltranspeptidase; membrane-plasma3. acetyltransferases; cytosolic
PRODUCTS: mercapturic acids OOH
SG
OH
S CH2
CH
NH2
COOH
OH
S CH2
CH
NH
COOH
CH3
O
GSH
epoxide conjugategly-glu
mercapturic acid
AcCoA
CoA-SH
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Conjugation with AMINO ACIDS
SUBSTRATES: carboxylic acids
DONOR: glycine or glutamine
ENZYMES: 1. glycine-N-acyltransferase; mitochondria2. glutamine-N-acyltranferase; mitochondria
PRODUCTS: N-acylglycine; N-acylglutamine
COOH
O O
SCoA
O O
NH
CH2
COOH
NH2 CH2
COOH
ATP CoA-SH+
benzoic acid glycine hippuric acid
• first metabolite discovered in human urine (originally in horse urine)• control of toluene abuse
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BIOTRANSFORMATION: Phase III. („transport“)
Philosophical question: Are these enzymes really phase III, since they determinewhether drug will get in contact with phase I and phase II?
• important enzymes that control import/export of the drug from the cells• regulation of uptake/efflux• membrane proteins• new approaches to drug design and discovery
• PGP = p-glycoprotein – pumps out drugs from the cells• OATP = organic anions transporting protein – regulates uptake of anionic drugs• OCTP = organic canions transporting protein – regulates uptake of canionic drugs
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METABOLISM OF AMPHETAMINE
CH2
CH
CH3
NH2
amphetamine
CH2
CH
CH3
NH2OH
CH2
CH
CH3
NH
OH
CH2
CH3
N
OH
CH2
CH3
NH2
OH
CH CH
CH3
NH2
OH
CH CH
CH3
NH2OH
OH
conjugates
CH2
CH3
NH
CH2
CH3
O glucuronideCH2
CH
CH3
OH
COOH
CONHCH2COOH
CH
CH3
O SO3H
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METABOLISM OF ETHANOL
• 90% degraded in the LIVER
CH3 CH2
OH CH3 CH
O CH3 O
O
ethanol acetaldehyde acetate
aldehyde dehydrogenase(cytosol; mitochondria)
NAD+ NADH + H+
alcohol dehydrogenase(cytosol)
NAD+ NADH + H+
NADP+NADPH
CYP2E1; MEOS; Endopl. Ret.
catalase; peroxisomes
H2O2H2O AcetylSCoATCA cycle
Toxic effects of ethanol:• disturbance of liver cell metabolism (NAD+ ----- NADH)• high reactivity of acetaldehyde – adducts with macromolecules• induction of microsomal system (chronic uptake) – radical production, activation of carcinogenes
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PERTURBATION OF METABOLISM BY ETHANOL
CH3 CH2
OH CH3 O
O
ethanol acetate
ADH; ALDH
2 x NAD+ 2 x NADH + 2 x H +
dihydroxyacetonephosphate
glycerol3-phosphate
TAG synthesis
Fatty acids
Not availablefor ββββ-oxidation
PYRUVATELACTATE
storage in liverSTEATOSIS
LACTATE ACIDOSIS
HYPERURICEMIA
Not available forgluconeogenesis
HYPOGLYCEMIA
Oxal acetate acetylSCoA
KETO ACIDOSIS
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TOXIC EFFECTS OF ACETALDEHYDE
ACETALDEHYDE HS-protein+ ACETALDEHYDE-S-protein
ADDUCT FORMATION• with microtubules – decrease in secretion of plasma proteins = accumulationof proteins in liver = liver enlargement = HEPATOMEGALY
• with some proteins – adducts = antigen properties = immune response = cytokinesALCOHOLIC HEPATITIS
• with ornitine decarboxylase – decrease in enzyme activity = diminution of cellproliferation = RETARDED REGENERATION OF DAMAGED LIVER
• with GSH – decrease in GSH level = increased lipid peroxidation of hepatocytemembranes = CELL DEATH
Transcriptional level – increase of collagen synthesis = FIBROSIS - CIRRHOSIS
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METABOLISM OF POLYAROMATIC HYDROCARBONSbenzpyrene
O
arene epoxideNAPD+NADPH + H+
P450s
OH
OH
H2O
arene diol
OHphenol
UDPGAPAPS
UDPGAPAPS
CONJUGATES - glucuronides- sulphates
excretion
OH
OHO
NAPD+
NADPH + H+
P450s
arene diol epoxide
GSH
GS
OH
glutathione conjugateGSH
mercapturicacid
excretion
• reactive intermediates – covalent binding to DNA (guanin e) and proteins (-SH) –strong carcinogenes
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Regulation of Drug Metabolizing Enzymes
• transcriptional regulation – controlled by „xenoreceptors“
• Aryl Hydrocarbon Receptor (AhR) = dioxin receptor; first discovered xenoreceptor
• orphan receptors – they do not have natural endogenous ligandPXR – pregnane X receptorCAR – constitutive androstane receptor
• other receptors – functional and transcriptional cross-talk („tangle of networks“)VDR – vitamin D receptorRARs – retinoic acid receptors (ligand all-trans RA); forms α, β, γRXR – retinoic X receptor (ligand cis-RA); forms a, b, gGR – glucocorticoid receptorothers (e.g. FXR, LXR, SHP etc.)
• compounds which activate xenoreceptors (agonists; ligands) induce expressionof drug metabolizing enzymes phase I, II and III. - INDUCERS
• wide spectrum of structurally unrelated compounds – alkaloids, drugs, antibiotics,environmental polutants, cigarette smoke, food constituents etc.
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DRUG INTERACTIONS• pharmacodynamic are predictable whereas pharmacokinetic are not
• P450 INDUCTION – increase in enzyme number; accelerated metabolism• P450 INHIBITION – decrease in enzyme activity; retardation of metabolism
• EXAMPLE 1 : cyclosporin A + ketoconazole = immune supressive cyclosporine Ais metabolized by CYP3A4. Antifungicide ketoconazole is strong inhibitor ofCYP3A4. When the two drugs are administered together, i.e. in transplant patients,cyclosporine metabolism is reduced, and patient suffer/die due to cyclosporinenephrotoxicity. Solution: decrease the dose of cyclosporine A.
• EXAMPLE 2 : cyclosporin A + rifampicin = immune supressive cyclosporine Ais metabolized by CYP3A4. Antibiotic rifampicin is strong inducer of CYP3A4.When the two drugs are administered together, cyclosporine metabolism isaccelerated, and patient suffer/die due to organ rejection (not enough CsA).Solution: increase the dose of cyclosporine A.
• EXAMPLE 3 : Drinking too much of alcohol = induction of CYP2E1. The day after,taking a pill of paracetamol. Paracetamol is converted by CYP2E1 to hepatotoxicquinone. Heeling hang-over with paracetamol increased the risk of liver damage!!!
• EXAMPLE 4 : Cigarette smoke contains PAHs - PAHs induce CYP1A1/2 in lung-CYP1A1/2 converts PAHs to carcinogenes – lung cancer!!! (similarly grilled meatcontains PAHs that induce intestinal CYP1A1/2 – conversion to carcinogenes –colorectal cancer!!!
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Regulation of Drug Metabolizing Enzymes
GR
CARPXR
CYP2A6 CYP2C8
CYP2B6 CYP2C9
AhR
CYP1A1 CYP1A2
CYP1B1
CYP3A4 CYP2C19
N-AcT
Phase II Phase III
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Signaling by AhR
DREDREDREDRE
AhRhsp90
hsp90p23
XAP2L
L
L
L
L
L LL
LL
AhRhsp90
hsp90p23
XAP2
L
hsp90
hsp90p23
XAP2
AhRL
ARNT
CYP1CYP1CYP1CYP1A1AhR
LARNT