Metabolism of xenobiotics of human environments.

Xenobiotics have been defined as chemicals to which an organism is exposed that are extrinsic to the normal metabolism of that organism. Without metabolism, many xenobiotics would reach toxic concentrations. Most metabolic activity inside the cell requires energy, cofactors, and enzymes in order to occur. Xenobiotic-metabolizing enzymes can be divided into phase I, phase II, and transporter enzymes. Lipophilic xenobiotics are often first metabolized by phase I enzymes, which function to make xenobiotics more polar and provide sites for conjugation reactions. Phase II enzymes are conjugating enzymes and can directly interact with xenobiotics but more commonly interact with metabolites produced by phase I enzymes. Through both passive and active transport, these more polar metabolites are eliminated. Most xenobiotics are cleared through multiple enzymes and pathways. The relationship between chemical concentrations, enzyme affinity and quantity, and cofactor availability often determine which metabolic reactions dominate in a given individual.

[1]  Stephen R. Johnson,et al.  Molecular properties that influence the oral bioavailability of drug candidates. , 2002, Journal of medicinal chemistry.

[2]  C. Wolf,et al.  Human cytochrome P450 enzyme selectivities in the oxidation of chlorinated benzenes. , 1995, Toxicology and applied pharmacology.

[3]  S. Spector,et al.  Efavirenz Pharmacokinetics in HIV-1-Infected Children Are Associated With CYP2B6-G516T Polymorphism , 2007, Journal of acquired immune deficiency syndromes.

[4]  E. Hodgson,et al.  Sulfoxidation of thioether-containing pesticides by the flavin-adenine dinucleotide- dependent monooxygenase of pig liver microsomes. , 1982, Biochemical pharmacology.

[5]  Yoshiro Saito,et al.  Population differences in major functional polymorphisms of pharmacokinetics/pharmacodynamics-related genes in Eastern Asians and Europeans: implications in the clinical trials for novel drug development. , 2012, Drug metabolism and pharmacokinetics.

[6]  Y. Sugiyama,et al.  Prediction of in vivo drug-drug interactions based on mechanism-based inhibition from in vitro data: inhibition of 5-fluorouracil metabolism by (E)-5-(2-Bromovinyl)uracil. , 2000, Drug metabolism and disposition: the biological fate of chemicals.

[7]  J. Goldstein,et al.  Metabolism of chlorpyrifos by human cytochrome P450 isoforms and human, mouse, and rat liver microsomes. , 2001, Drug metabolism and disposition: the biological fate of chemicals.

[8]  J. Cashman,et al.  A nomenclature for the mammalian flavin-containing monooxygenase gene family based on amino acid sequence identities. , 1994, Archives of biochemistry and biophysics.

[9]  A. Tayel,et al.  Infants exposure to aflatoxin M₁ as a novel foodborne zoonosis. , 2011, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[10]  E. Hodgson,et al.  Physiological factors affecting protein expression of flavin-containing monooxygenases 1, 3 and 5. , 1998, Xenobiotica; the fate of foreign compounds in biological systems.

[11]  P. Taylor,et al.  Acetylcholinesterase active centre and gorge conformations analysed by combinatorial mutations and enantiomeric phosphonates. , 2003, The Biochemical journal.

[12]  J. Sussman,et al.  Acetylcholinesterase: from 3D structure to function. , 2010, Chemico-biological interactions.

[13]  J. M. Shekosky,et al.  Metabolism in dogs of the chloro- and trifluoromethyl-analogues of a piperazine-substituted dihydrobenzoxazepine. , 1971, Xenobiotica; the fate of foreign compounds in biological systems.

[14]  D. Ziegler Chapter 9 – Microsomal Flavin-Containing Monooxygenase: Oxygenation of Nucleophilic Nitrogen and Sulfur Compounds , 1980 .

[15]  G. Livesey,et al.  Whole body metabolism is not restricted to D-sugars because energy metabolism of L-sugars fits a computational model in rats. , 1995, The Journal of nutrition.

[16]  R. Mailman,et al.  Cytochrome P-450 difference spectra: effect of chemical structure on type II spectra in mouse hepatic microsomes. , 1974, Drug metabolism and disposition: the biological fate of chemicals.

[17]  Oxidation of pesticides by purified cytochrome P-450 isozymes from mouse liver. , 1985, Toxicology letters.

[18]  A. Rettie,et al.  Human Hepatic Flavin-Containing Monooxygenases 1 (FMO1) and 3 (FMO3) Developmental Expression , 2002, Pediatric Research.

[19]  E. De Clercq,et al.  Antiadenovirus Activities of Several Classes of Nucleoside and Nucleotide Analogues , 2005, Antimicrobial Agents and Chemotherapy.

[20]  F. Oesch,et al.  Epoxide hydrolases: structure, function, mechanism, and assay. , 2005, Methods in enzymology.

[21]  E. Hodgson,et al.  The metabolism of insecticides: the role of monooxygenase enzymes. , 1984, Annual review of pharmacology and toxicology.

[22]  A. Rettie,et al.  Identification of enzymes involved in the metabolism of atrazine, terbuthylazine, ametryne, and terbutryne in human liver microsomes. , 1997, Chemical research in toxicology.

[23]  H. Glaeser,et al.  Molecular Mechanisms of Polymorphic CYP3A7 Expression in Adult Human Liver and Intestine* , 2002, The Journal of Biological Chemistry.

[24]  Stacy L. Gelhaus,et al.  Metabolism of benzo[a]pyrene in human bronchoalveolar H358 cells using liquid chromatography-mass spectrometry. , 2007, Chemical research in toxicology.

[25]  M. Fraaije,et al.  Revealing the moonlighting role of NADP in the structure of a flavin-containing monooxygenase , 2008, Proceedings of the National Academy of Sciences.

[26]  M. Parker,et al.  Crystal structure of maleylacetoacetate isomerase/glutathione transferase zeta reveals the molecular basis for its remarkable catalytic promiscuity. , 2001, Biochemistry.

[27]  A. Sarmah,et al.  Dissipation and sorption of six commonly used pesticides in two contrasting soils of New Zealand , 2009, Journal of environmental science and health. Part. B, Pesticides, food contaminants, and agricultural wastes.

[28]  William B. Jakoby,et al.  Enzymatic basis of detoxication , 1980 .

[29]  E. Hodgson,et al.  Oxidation of pesticides by purified microsomal FAD-containing monooxygenase from mouse and pig liver , 1985 .

[30]  L. Zhang,et al.  Assessment of the Impact of Renal Impairment on Systemic Exposure of New Molecular Entities: Evaluation of Recent New Drug Applications , 2009, Clinical pharmacology and therapeutics.

[31]  D. G. McCarver,et al.  The ontogeny of human drug-metabolizing enzymes: phase I oxidative enzymes. , 2002, The Journal of pharmacology and experimental therapeutics.

[32]  Ronald N Hines,et al.  The ontogeny of drug metabolism enzymes and implications for adverse drug events. , 2008, Pharmacology & therapeutics.

[33]  S. Landi Mammalian class theta GST and differential susceptibility to carcinogens: a review. , 2000, Mutation research.

[34]  E. Hodgson,et al.  Metabolism of insecticides by mixed function oxidase systems. , 1980, Pharmacology & therapeutics.

[35]  C. G. Schmiterlow,et al.  Physiological disposition and fate of C14-labelled nicotine in mice and rats. , 1962, The Journal of pharmacology and experimental therapeutics.

[36]  D. G. McCarver,et al.  The ontogeny of human drug-metabolizing enzymes: phase II conjugation enzymes and regulatory mechanisms. , 2002, The Journal of pharmacology and experimental therapeutics.

[37]  B. Arison,et al.  Identification of cytochrome P4503A4 as the major enzyme responsible for the metabolism of ivermectin by human liver microsomes. , 1998, Xenobiotica; the fate of foreign compounds in biological systems.

[38]  E. Hodgson,et al.  In vitro studies of the metabolism of atrazine, simazine, and terbutryn in several vertebrate species. , 1990 .

[39]  E. Hodgson,et al.  6 – Metabolism of Organophosphorus Compounds by the Flavin-Containing Monooxygenase , 1992 .

[40]  F. Shanahan,et al.  The gut flora as a forgotten organ , 2006, EMBO reports.

[41]  B. Kelly,et al.  Flesh residue concentrations of organochlorine pesticides in farmed and wild salmon from British Columbia, Canada , 2011, Environmental toxicology and chemistry.

[42]  G R Lankas,et al.  P-glycoprotein deficiency in a subpopulation of CF-1 mice enhances avermectin-induced neurotoxicity. , 1997, Toxicology and applied pharmacology.

[43]  K. Nakachi,et al.  Polymorphisms of the CYP1A1 and glutathione S-transferase genes associated with susceptibility to lung cancer in relation to cigarette dose in a Japanese population. , 1993, Cancer research.

[44]  H. Pols,et al.  A common polymorphism in the CYP3A7 gene is associated with a nearly 50% reduction in serum dehydroepiandrosterone sulfate levels. , 2005, The Journal of clinical endocrinology and metabolism.

[45]  J. Casida,et al.  Insecticide Metabolism, Nature of Certain Carbamate Metabolites of Insecticide Sevin , 1964 .

[46]  H. W. Dorough Metabolism of Furadan (NIA-10242) in rats and houseflies , 1968 .

[47]  A. Aceto,et al.  Binding of pesticides to alpha, mu and pi class glutathione transferase. , 1995, Toxicology letters.

[48]  W. Humphreys,et al.  Identification of the Human Enzymes Involved in the Oxidative Metabolism of Dasatinib: An Effective Approach for Determining Metabolite Formation Kinetics , 2008, Drug Metabolism and Disposition.

[49]  H. Jinno,et al.  In vitro metabolism of chlorotriazines: characterization of simazine, atrazine, and propazine metabolism using liver microsomes from rats treated with various cytochrome P450 inducers. , 1999, Toxicology and applied pharmacology.

[50]  N. Motoyama Glutathione S-transferases: their role in the metabolism of organophosphorus insecticides. , 1980 .

[51]  M. Sauvant-Rochat,et al.  What is the best biomarker to assess arsenic exposure via drinking water? , 2012, Environment international.

[52]  L. Gakhar,et al.  Novel, Highly Specific N-Demethylases Enable Bacteria To Live on Caffeine and Related Purine Alkaloids , 2012, Journal of bacteriology.

[53]  Manfred Kansy,et al.  Predicting plasma protein binding of drugs: a new approach. , 2002, Biochemical pharmacology.

[54]  E. Hodgson,et al.  In vitro metabolism of alachlor by human liver microsomes and human cytochrome P450 isoforms. , 1999, Chemico-biological interactions.

[55]  M. Schwab,et al.  Aberrant Splicing Caused by Single Nucleotide Polymorphism c.516G>T [Q172H], a Marker of CYP2B6*6, Is Responsible for Decreased Expression and Activity of CYP2B6 in Liver , 2008, Journal of Pharmacology and Experimental Therapeutics.

[56]  T. Eling,et al.  Co-oxidation of benzidine by prostaglandin synthase and comparison with the action of horseradish peroxidase. , 1983, The Journal of biological chemistry.

[57]  E. Hodgson,et al.  Magnitude of involvement of the mammalian flavin-containing monooxygenase in the microsomal oxidation of pesticides , 1985 .

[58]  N. Vermeulen,et al.  Genetic polymorphisms of human N-acetyltransferase, cytochrome P450, glutathione-S-transferase, and epoxide hydrolase enzymes: relevance to xenobiotic metabolism and toxicity. , 1999, Critical reviews in toxicology.

[59]  A. Tward,et al.  Expression of human paraoxonase (PON1) during development. , 2003, Pharmacogenetics.

[60]  Ernest Hodgson,et al.  IN VITRO METABOLISM OF NAPHTHALENE BY HUMAN LIVER MICROSOMAL CYTOCHROME P450 ENZYMES , 2006, Drug Metabolism and Disposition.

[61]  Jorma Toppari,et al.  Human Breast Milk Contamination with Phthalates and Alterations of Endogenous Reproductive Hormones in Infants Three Months of Age , 2005, Environmental health perspectives.

[62]  E. Hodgson,et al.  Metabolism of phosphorus-containing compounds by pig liver microsomal FAD-containing monooxygenase. , 1985, Biochemical pharmacology.

[63]  F. Perera,et al.  Genetic monitoring of human polymorphic cancer susceptibility genes by polymerase chain reaction: application to glutathione transferase mu. , 1992, Environmental health perspectives.

[64]  J. Aronson,et al.  The disposition and metabolism of sulphasalazine (salicylazosulphapyridine) in man. , 1982, British journal of clinical pharmacology.

[65]  Patrick S. Callery,et al.  Cysteine S-conjugate β-lyases: important roles in the metabolism of naturally occurring sulfur and selenium-containing compounds, xenobiotics and anticancer agents , 2011, Amino Acids.

[66]  E. Hodgson,et al.  Comparative metabolism of chloroacetamide herbicides and selected metabolites in human and rat liver microsomes. , 2000, Environmental health perspectives.

[67]  M. Mikov The metabolism of drugs by the gut flora , 1994, European Journal of Drug Metabolism and Pharmacokinetics.

[68]  C. V. Van horn,et al.  Energy Availability and Alcohol-Related Liver Pathology , 2003, Alcohol research & health : the journal of the National Institute on Alcohol Abuse and Alcoholism.

[69]  E. Hodgson,et al.  Flavin adenine dinucleotide--dependent monooxygenase: its role in the sulfoxidation of pesticides in mammals. , 1980, Science.

[70]  G R Lankas,et al.  Placental P-glycoprotein deficiency enhances susceptibility to chemically induced birth defects in mice. , 1998, Reproductive toxicology.

[71]  H. Jörnvall,et al.  Identification of three classes of cytosolic glutathione transferase common to several mammalian species: correlation between structural data and enzymatic properties. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[72]  H. Inui,et al.  Herbicide Metabolism and Cross-Tolerance in Transgenic Potato Plants Co-Expressing Human CYP1A1, CYP2B6, and CYP2C19 , 2000 .

[73]  P. Kostyniak,et al.  Human Hepatic Cytochrome P450-Specific Metabolism of Parathion and Chlorpyrifos , 2007, Drug Metabolism and Disposition.

[74]  F. Guengerich,et al.  Chemical mechanisms of catalysis by cytochromes P-450: a unified view , 1984 .

[75]  B. Ring,et al.  Comparative metabolic capabilities of CYP3A4, CYP3A5, and CYP3A7. , 2002, Drug metabolism and disposition: the biological fate of chemicals.

[76]  E. Hodgson,et al.  Flavin-containing monooxygenase and cytochrome P450 mediated metabolism of pesticides: from mouse to human. , 1998 .

[77]  Elizabeth A. Lowenhaupt,et al.  Psychosis in a 12-year-old HIV-positive girl with an increased serum concentration of efavirenz. , 2007, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[78]  J. Stevens,et al.  Epirubicin Glucuronidation and UGT2B7 Developmental Expression , 2006, Drug Metabolism and Disposition.

[79]  K. Pittman,et al.  Mirex kinetics in the rhesus monkey. I. Disposition and excretion. , 1976, Drug metabolism and disposition: the biological fate of chemicals.

[80]  J. Caldwell,et al.  An Introduction to Drug Disposition: The Basic Principles of Absorption, Distribution, Metabolism, and Excretion , 1995, Toxicologic pathology.

[81]  T. Eling,et al.  Xenobiotic metabolism by prostaglandin endoperoxide synthetase. , 1983, Drug metabolism reviews.

[82]  A. Ghose,et al.  A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. , 1999, Journal of combinatorial chemistry.

[83]  E. Hodgson,et al.  Metabolism of Endosulfan-α by Human Liver Microsomes and Its Utility as a Simultaneous in Vitro Probe for CYP2B6 and CYP3A4 , 2006, Drug Metabolism and Disposition.

[84]  R. Saalfrank,et al.  In vitro metabolism of atrazine, terbuthylazine, ametryne, and terbutryne in rats, pigs, and humans. , 1996, Drug metabolism and disposition: the biological fate of chemicals.

[85]  D. Nelson The Cytochrome P450 Homepage , 2009, Human Genomics.

[86]  M. Murray,et al.  Biotransformation of parathion in human liver: participation of CYP3A4 and its inactivation during microsomal parathion oxidation. , 1997, The Journal of pharmacology and experimental therapeutics.

[87]  Larry D. Claxton,et al.  The Salmonella Mutagenicity Assay: The Stethoscope of Genetic Toxicology for the 21st Century , 2010, Environmental health perspectives.

[88]  F. Lombardo,et al.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. , 2001, Advanced drug delivery reviews.

[89]  J. Magdalou,et al.  Metabolism of tridiphane (2-(3,5-dichlorophenyl)-2(2,2,2-trichloroethyl)oxirane) by hepatic epoxide hydrolases and glutathione S-transferases in mouse. , 1987, Toxicology and applied pharmacology.

[90]  J. Fukami Metabolism of several insecticides by glutathion S-transferase. , 1980, Pharmacology & therapeutics.

[91]  R. Pero,et al.  The hereditary transmission of high glutathione transferase activity towards trans-stilbene oxide in human mononuclear leukocytes , 2004, Human Genetics.

[92]  A. Gaedigk,et al.  Variability in drug metabolizing enzyme activity in HIV-infected patients , 2010, European Journal of Clinical Pharmacology.

[93]  D. Nelson,et al.  Evolution of the cytochrome P450 genes. , 1989, Xenobiotica; the fate of foreign compounds in biological systems.

[94]  D. Saleh,et al.  GSTM1, GSTT1 Null Variants, and GPX1 Single Nucleotide Polymorphism Are Not Associated with Bladder Cancer Risk in Egypt , 2011, Cancer Epidemiology, Biomarkers & Prevention.

[95]  K. Beckman,et al.  Paraoxonase Polymorphisms, Haplotypes, and Enzyme Activity in Latino Mothers and Newborns , 2006, Environmental health perspectives.

[96]  E. Conn,et al.  Amygdalin toxicity studies in rats predict chronic cyanide poisoning in humans. , 1981, The Western journal of medicine.

[97]  H. Yokota,et al.  Excretion of bisphenol A-glucuronide into the small intestine and deconjugation in the cecum of the rat. , 2002, Biochimica et biophysica acta.

[98]  E. De Clercq,et al.  Antiviral agents acting as DNA or RNA chain terminators. , 2009, Handbook of experimental pharmacology.

[99]  Shiew-Mei Huang,et al.  Scientific perspectives on drug transporters and their role in drug interactions. , 2006, Molecular pharmaceutics.

[100]  H. McLeod,et al.  A Novel Duplication Type of CYP2A6 Gene in African-American Population , 2007, Drug Metabolism and Disposition.

[101]  David E. Williams,et al.  Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism. , 2005, Pharmacology & therapeutics.

[102]  E. Hodgson,et al.  Metabolism of Toxicants , 2004 .

[103]  A. Sabbagh,et al.  Arylamine N-Acetyltransferase 2 (NAT2) Genetic Diversity and Traditional Subsistence: A Worldwide Population Survey , 2011, PloS one.

[104]  R. Mailman,et al.  The cytochrome P-450 Substrate optical difference spectra of pesticides with mouse hepatic microsomes , 1972, Bulletin of environmental contamination and toxicology.

[105]  E. Hodgson,et al.  Molecular Cloning, Sequence, and Expression of Mouse Flavin‐Containing Monooxygenases 1 and 5 (FMO1 and FMO5) , 1998, Journal of biochemical and molecular toxicology.

[106]  E. Hodgson,et al.  Stereospecificity in the oxidation of phorate and phorate sulphoxide by purified FAD-containing mono-oxygenase and cytochrome P-450 isozymes. , 1988, Xenobiotica; the fate of foreign compounds in biological systems.

[107]  E. Hodgson,et al.  Human variation in CYP-specific chlorpyrifos metabolism. , 2010, Toxicology.