Xenobiotics and Biotransformation

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XENOBIOTICS:

XENOBIOTICS Chem 245 – Chemistry of Nucleic Acids Dan Lester Ecleo dan_ecleo@yahoo.com University of San Carlos – Cebu City, Philippines

Xenobiotics:

Chemical which is found in an organism but which is not normally produced or expected to be present in it Comes from the greek words: ξένος ( xenos ) – foreigner, stranger βίος ( bios, vios ) – life Definition Xenobiotics

Xenobiotics:

Xenobiotics Drugs, antibiotics Organochlorides Examples Benzene polychlorinated biphenyls (PCBs) polycyclic aromatic hydrocarbons (PAHs)

Xenobiotics:

Xenobiotics Causes chromosomal abberations in the peripheral blood leukocytes and bone marrow Benzene oxide – not excreted readily and can interact with DNA Benzene

Xenobiotics:

Xenobiotics Class of organic compounds with 1 to 10 chlorine atoms attached to a biphenyl Polychlorinated biphenyl (PCB) Odorless, tasteless, clear to pale yellow, viscous liquids High thermal conductivity

Xenobiotics:

Xenobiotics Chemically fairly inert, stable compounds Readily penetrate skin Yusho Disease (1968) Polychlorinated biphenyl (PCB)

Xenobiotics:

Xenobiotics Chemical compounds that consists of fused aromatic rings and do not contain heteroatoms or carry substituents . PAHs occur in oil, coal and tar deposits, and are produced as byproducts of fuel burning Polycyclic aromatic hydrocarbon(PAH)

Xenobiotics:

Xenobiotics Polycyclic aromatic hydrocarbon(PAH) Anthracene Benzo [a] pyrene Chrysene Corannulene Coronene Naphthacene Naphthalene Ovalene Pentacene Phenanthrene Pyrene Triphenylene EXAMPLES

Xenobiotics:

Xenobiotics Anthracene Polycyclic aromatic hydrocarbon(PAH) Anthracene Benzo [a] pyrene Chrysene Corannulene Coronene Naphthacene Naphthalene Ovalene Pentacene Phenanthrene Pyrene Triphenylene EXAMPLES Chronic exposure may lead to inflammation of the gastrointestinal tract, patchy areas of increased yellow– brown pigment changes, loss of skin pigment, thinning or patchy thickening of skin, skin warts, skin cancer, and pimples

Xenobiotics:

Xenobiotics Benzo [a] pyrene Polycyclic aromatic hydrocarbon(PAH) Anthracene Benzo [a] pyrene Chrysene Corannulene Coronene Naphthacene Naphthalene Ovalene Pentacene Phenanthrene Pyrene Triphenylene EXAMPLES There is some evidence that it causes skin, lung, and bladder cancer in humans and animals. Since tobacco smoke contains BP, smoking may increase the risk of lung cancer with exposure to BP.

Xenobiotics:

Xenobiotics Chrysene Polycyclic aromatic hydrocarbon(PAH) Anthracene Benzo [a] pyrene Chrysene Corannulene Coronene Naphthacene Naphthalene Ovalene Pentacene Phenanthrene Pyrene Triphenylene EXAMPLES The primary toxic effect of concern for chrysene is carcinogenicity, which is most likely the result of the mutagenic activity of its metabolites, 1,2-dihydrodiol and 1,2-diol-3,4-epoxide.

Xenobiotics:

Xenobiotics Corannulene Polycyclic aromatic hydrocarbon(PAH) Anthracene Benzo [a] pyrene Chrysene Corannulene Coronene Naphthacene Naphthalene Ovalene Pentacene Phenanthrene Pyrene Triphenylene EXAMPLES

Xenobiotics:

Xenobiotics Coronene Polycyclic aromatic hydrocarbon(PAH) Anthracene Benzo [a] pyrene Chrysene Corannulene Coronene Naphthacene Naphthalene Ovalene Pentacene Phenanthrene Pyrene Triphenylene EXAMPLES

Xenobiotics:

Xenobiotics Naphthacene Polycyclic aromatic hydrocarbon(PAH) Anthracene Benzo [a] pyrene Chrysene Corannulene Coronene Naphthacene Naphthalene Ovalene Pentacene Phenanthrene Pyrene Triphenylene EXAMPLES

Xenobiotics:

Xenobiotics Naphthalene Polycyclic aromatic hydrocarbon(PAH) Anthracene Benzo [a] pyrene Chrysene Corannulene Coronene Naphthacene Naphthalene Ovalene Pentacene Phenanthrene Pyrene Triphenylene EXAMPLES Systemic absorption of naphthalene vapor may result in cataracts. Removal of oxygen from the aqueous humor due to the autooxidation of 1,2-dihydroxynaphthalene may make the lens sensitive to naphthalene toxicity.

Xenobiotics:

Xenobiotics Ovalene Polycyclic aromatic hydrocarbon(PAH) Anthracene Benzo [a] pyrene Chrysene Corannulene Coronene Naphthacene Naphthalene Ovalene Pentacene Phenanthrene Pyrene Triphenylene EXAMPLES

Xenobiotics:

Xenobiotics Pentacene Polycyclic aromatic hydrocarbon(PAH) Anthracene Benzo [a] pyrene Chrysene Corannulene Coronene Naphthacene Naphthalene Ovalene Pentacene Phenanthrene Pyrene Triphenylene EXAMPLES

Xenobiotics:

Xenobiotics Phenanthrene Polycyclic aromatic hydrocarbon(PAH) Anthracene Benzo [a] pyrene Chrysene Corannulene Coronene Naphthacene Naphthalene Ovalene Pentacene Phenanthrene Pyrene Triphenylene EXAMPLES

Xenobiotics:

Xenobiotics Pyrene Polycyclic aromatic hydrocarbon(PAH) Anthracene Benzo [a] pyrene Chrysene Corannulene Coronene Naphthacene Naphthalene Ovalene Pentacene Phenanthrene Pyrene Triphenylene EXAMPLES It is also produced as a result of incomplete combustion in the exhaust of motor vehicles and engines, in cigarette smoke, and in stoves and furnaces. Pyrene is a skin, eye, and respiratory irritant. Pyrene is not classified as human carcinogen by the US Environmental Protection Agency (EPA)

Xenobiotics:

Xenobiotics Triphenylene Polycyclic aromatic hydrocarbon(PAH) Anthracene Benzo [a] pyrene Chrysene Corannulene Coronene Naphthacene Naphthalene Ovalene Pentacene Phenanthrene Pyrene Triphenylene EXAMPLES

Biotransformation:

Biotransformation Biotransformation is the process whereby a substance is changed from one chemical to another (transformed) by a chemical reaction within the body. Definition Phase I Phase II Consequences: Detoxification Metabolic Activation Purpose: Converts lipophilic to hydrophilic cpds Facilitates excretion Summary

Biotransformation:

Factors affecting Metabolism Biotransformation Definition Phase I Phase II Age Nutrition Immunologic Hormonal Gender Disease Genetic Pregancy Summary Organs involved in biotransformation Liver Lung Kidney Intestine Skin Gonads

Biotransformation:

Biotransformation Exposing functional groups Transforms lipophilic xenobiotics into hydrophilic metabolites Phase I reactions include oxidation, reduction and hydrolysis Membrane bound (ER) Phase I Phase II Phase I Oxidation Reduction Hydrolysis Summary

Biotransformation:

Biotransformation Phase I enzymes: Alcohol dehydrogenase Aldehyde dehydrogenase Aldehyde oxidase Cytochrome P450 monooxygenases Flavin -containing monooxygenases Monoamine oxidase Xanthine oxidase Esterases Phase I Phase II Phase I Oxidation Reduction Hydrolysis Summary

Biotransformation:

Biotransformation Examples of reactions catalyzed by oxidases Oxidation Phase I Phase II Oxidation Reduction Hydrolysis Summary

Biotransformation:

Biotransformation Examples of reactions catalyzed by oxidases Phase I Phase II Oxidation Reduction Hydrolysis Oxidation Summary

Biotransformation:

Biotransformation Examples of reactions catalyzed by flavin monooxygenases (FMO) Oxidation Phase I Phase II Oxidation Reduction Hydrolysis Summary

Biotransformation:

Biotransformation Examples of reactions catalyzed by flavin monooxygenases (FMO) Phase I Phase II Oxidation Reduction Hydrolysis Oxidation Summary

Biotransformation:

Biotransformation Activation of benzene to myelotoxic metabolites Oxidation Phase I Phase II Oxidation Reduction Hydrolysis Summary

Biotransformation:

Biotransformation Types of reductions: Azo reductions Nitro reduction Carbonyl reduction Disulfide reduction Sulfoxide reduction Quinone reduction Dehalogenation Reduction Phase I Phase II Oxidation Reduction Hydrolysis Summary

Biotransformation:

Biotransformation Reduction of xenobiotics by carbonyl reductase (A) and alcohol dehydrogenase (B) Reduction Phase I Phase II Oxidation Reduction Hydrolysis Summary

Biotransformation:

Biotransformation Example of drugs that undergo azo reduction Reduction Phase I Phase II Oxidation Reduction Hydrolysis Summary

Slide 33:

Examples of drugs that undergo nitro reduction Phase I Phase II Oxidation Reduction Hydrolysis Reduction Summary

Biotransformation:

Biotransformation Role of epoxide hydrolase in the inactivation of benzo [a] pyrene and in the coversion of benzo [a] pyrene to its tumorigenic diolepoxide Hydrolysis Phase I Phase II Oxidation Reduction Hydrolysis Summary

Biotransformation:

Summary Biotransformation Role of epoxide hydrolase in the inactivation of benzo [a] pyrene and in the coversion of benzo [a] pyrene to its tumorigenic diolepoxide Hydrolysis Phase I Phase II Oxidation Reduction Hydrolysis

Biotransformation:

Biotransformation Conjugation reactions Non membrane-bound Addition of polar groups Xenobiotic metabolites increase in molecular weight and hydrophilicity For these reactions to occur, a functional group must be present on either the parent compound or its phase I product Phase I Phase II Phase II Glucoronidation Sulphation Acetylation AA conjugation Methylation Summary

Biotransformation:

Biotransformation Four primary enzymes: Glucoronosyltransferase Sulfotransferase Glutathione-S- transferase Acetyltransferase Phase I Phase II Glucoronidation Sulphation Acetylation AA conjugation Methylation Summary Phase II

Biotransformation:

Biotransformation Glucoronidation Phase I Phase II Glucoronidation Sulphation Acetylation AA conjugation Methylation Summary

Biotransformation:

Biotransformation Glucoronidation Phase I Phase II Glucoronidation Sulphation Acetylation AA conjugation Methylation Summary

Biotransformation:

Biotransformation Sulphation Phase I Phase II Glucoronidation Sulphation Acetylation AA conjugation Methylation Summary

Biotransformation:

Biotransformation Acetylation Phase I Phase II Glucoronidation Sulphation Acetylation AA conjugation Methylation Summary

Biotransformation:

Biotransformation Glutathione conjugation Amino acid conjugation Phase I Phase II Glucoronidation Sulphation Acetylation AA conjugation Methylation Summary Reduced glutathione

Biotransformation:

Biotransformation Glutathione conjugation Amino acid conjugation Phase I Phase II Glucoronidation Sulphation Acetylation AA conjugation Methylation Summary

Biotransformation:

Biotransformation Glutathione conjugation Amino acid conjugation Phase I Phase II Glucoronidation Sulphation Acetylation AA conjugation Methylation Summary

Biotransformation:

Biotransformation Methylation Phase I Phase II Glucoronidation Sulphation Acetylation AA conjugation Methylation Summary

Biotransformation:

Biotransformation Phase I Phase II Summary Summary

Cytochrome P450:

Cytochrome P450 The cytochrome P450 enzyme system consists of a superfamily of hemoproteins that catalyze the oxidative metabolism of a wide range of exogenous and endogenous compounds Structure Properties Nomenclature Functions

Cytochrome P450:

Cytochrome P450 Structure Structure Properties Nomenclature Functions

Cytochrome P450:

Cytochrome P450 Nomenclature Structure Properties Nomenclature Functions CYP 3 A 4 Family Sub-family Individual gene/ isoenzyme / isozyme / isoform Cytochrome P450

Cytochrome P450:

Cytochrome P450 Can metabolize many xenobiotics Can catalyze many types of reactions Widely distributed among tissues Exists in multiple forms Properties Structure Properties Nomenclature Functions

Cytochrome P450:

Cytochrome P450 Functions Structure Properties Nomenclature Functions

Slide 52:

Structure Properties Nomenclature Functions Functions

References:

References Wikipedia (http://en.wikipedia.org) Encyclopedia of Toxicology, 2 nd edition (Four-volume) Phase II Metabolism. Mike Hooper Xenobiotic Biotransformation. Michael A. Trush . Johns Hopkins University Oxidative metabolic profiling of xenobiotics by human P450s expressed in tobacco cell suspension cultures. B. Schmidt, N. Joussen, M. Bode and I. Schuphan Organic contaminants and metabolism of xenobiotics Cytochrome P450 and drug interactions. D.K. BADYAL, A.P. DADHICH. Indian Journal of Pharmacology 2001; 33: 248-259 Cytochromes P450 – their impact on drug treatment. Michael Tredger and Sarah Stoll Biotransformation – Xenobiotic metabolism. Essentials of Toxicology. Klaassen , Curtis D. and Watkins, John B

Abbreviations:

Abbreviations UDP – Uridine diphosphate PAPS – 3’-phosphoadenosine-5’-phosphosulfate NAT – N- acetyl transferase PHS – Prostaglandin H synthase SAM – S- adenosyl methionine