Abstract
Biotransformation is essential to convert lipophilic chemicals to water-soluble and readily excretable metabolites. Formally, biotransformation reactions are classified into phase I and phase II reactions. Phase I reactions represent the introduction of functional groups, whereas phase II reactions are conjugations of such functional groups with endogenous, polar products. Biotransformation also plays an essential role in the toxicity of many chemicals due to the metabolic formation of toxic metabolites. These may be classified as stable but toxic products, reactive electrophiles, radicals, and reactive oxygen metabolites. The interaction of toxic products formed by biotransformation reactions with cellular macromolecules initiates the sequences resulting in cellular damage, cell death and toxicity.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Medinsky M, Valentine JL (2001) Toxicokinetics. In: CD Klaassen (ed.): Casarett and Doull’s Toxicology. The Basic Science of Poisons. McGraw-Hill, New York, 225–237
May DG (1994) Genetic differences in drug disposition. J Clin Pharmacol 34: 881–897
Pang KS, Xu X, St-Pierre MV (1992) Determinants of metabolite disposition. Annu Rev Pharmacol Toxicol 32: 623–669
Filser JG (2008) Toxicokinetics. In: H Greim, R Snyder (eds): Toxicology and Risk Assessment. John Wiley & Sons, Hoboken, 19–49
Gibson GG, Skett P (2001) Introduction to Drug Metabolism. Nelson Thornes, Cheltenham
Guengerich FP (2006) Cytochrome P450s and other enzymes in drug metabolism and toxicity. AAPS J 8: E101–111
Buters JTM (2008) Phase I metabolism. In: H Greim, R Snyder (eds): Toxicology and Risk Assessment. John Wiley & Sons, Hoboken, 49–74
Anders MW (1985) Bioactivation of Foreign Compounds. Academic Press, New York
Anders MW (1988) Bioactivation mechanisms and hepatocellular damage. In: IM Arias, WB Jakoby, H Popper, D Schachter, DA Shafritz (eds): The Liver: Biology and Pathology, 2nd edition. Raven Press, New York, 389–400
DeBethizy JD, Hayes JR (1994) Metabolism, a determinant of toxicity. In: AW Hayes (ed.): Principles and Methods of Toxicology. Raven Press, New York, 59–100
Guengerich FP (1991) Reactions and significance of cytochrome P450 enzymes. J Biol Chem 266: 10019–10022
Guengerich FP (2008) Cytochrome P450 and chemical toxicology. Chem Res Toxicol 21: 70–83
Guengerich FP (2007) Mechanisms of cytochrome P450 substrate oxidation: MiniReview. J Biochem Mol Toxicol 21: 163–168
Ding X, Kaminsky LS (2003) Human extrahepatic cytochromes P450: Function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts. Annu Rev Pharmacol Toxicol 43: 149–173
Guengerich FP, Liebler DC (1985) Enzymatic activation of chemicals to toxic metabolites. CRC Crit Rev Toxicol 14: 259–307
Guengerich FP (2001) Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity. Chem Res Toxicol 14: 611–650
Rendic S, Di Carlo FJ (1997) Human cytochrome P450 enzymes: A status report summarizing their reactions, substrates, inducers, and inhibitors. Drug Metab Rev 29: 413–580
Brown CM, Reisfeld B, Mayeno AN (2008) Cytochromes P450: A structure-based summary of biotransformations using representative substrates. Drug Metab Rev 40: 1–100
Cashman JR (2003) The role of flavin-containing monooxygenases in drug metabolism and development. Curr Opin Drug Discov Dev 6: 486–493
Cashman JR, Zhang J (2006) Human flavin-containing monooxygenases. Annu Rev Pharmacol Toxicol 46: 65–100
Cashman JR (2005) Some distinctions between flavin-containing and cytochrome P450 monooxygenases. Biochem Biophys Res Commun 338: 599–604
Krueger SK, Williams DE (2005) Mammalian flavin-containing monooxygenases: Structure/function, genetic polymorphisms and role in drug metabolism. Pharmacol Ther 106: 357–387
Vogel C (2000) Prostaglandin H synthases and their importance in chemical toxicity. Curr Drug Metab 1: 391–404
Smith BJ, Curtis JF, Eling TE (1991) Bioactivation of xenobiotics by prostaglandin H synthase. Chem Biol Interact 79: 245–264
Kettle AJ, Winterbourn CC (1992) Oxidation of hydrochinone by myeloperoxidase. J Biol Chem 267: 8319–8324
Arand M, Cronin A, Oesch F, Mowbray SL, Jones TA (2003) The telltale structures of epoxide hydrolases. Drug Metab Rev 35: 365–383
Arand M, Cronin A, Adamska M, Oesch F (2005) Epoxide hydrolases: Structure, function, mechanism, and assay. Methods Enzymol 400: 569–588
Sheweita SA, Tilmisany AK (2003) Cancer and phase II drug-metabolizing enzymes. Curr Drug Metab 4: 45–58
Tukey RH, Strassburg CP (2000) Human UDP-glucuronosyltransferases: Metabolism, expression, and disease. Annu Rev Pharmacol Toxicol 40: 581–616
Burchell B, Coughtrie WH (1989) UPD-glucuronosyltransferases. Pharmacol Ther 43: 261–289
Tephly TR, Burchell B (1990) UDP-glucuronosyltransferases: A family of detoxifying enzymes. Trends Pharmacol Sci 11: 276–279
Duffel MW, Marshal AD, McPhie P, Sharma V, Jakoby WB (2001) Enzymatic aspects of the phenol (aryl) sulfotransferases. Drug Metab Rev 33: 369–395
Gamage N, Barnett A, Hempel N, Duggleby RG, Windmill KF, Martin JL, McManus ME (2006) Human sulfotransferases and their role in chemical metabolism. Toxicol Sci 90: 5–22
Knights KM, Sykes MJ, Miners JO (2007) Amino acid conjugation: Contribution to the metabolism and toxicity of xenobiotic carboxylic acids. Exp Opin Drug Metab Toxicol 3: 159–168
Ritter JK (2000) Roles of glucuronidation and UDP-glucuronosyltransferases in xenobiotic bioactivation reactions. Chem Biol Interact 129: 171–193
Bock KW, Bock-Hennig BS, Fischer G, Ullrich D (1984) Role of glucuronidation and sulfation in the control of reactive metabolites. In: H Greim, R Jung, M Kramer, H Marquardt, F Oesch (eds): Biochemical Basis of Chemical Carcinogenesis. Raven Press, New York, 13–22
Mulder GJ (1981) Sulfation of Drugs and Related Compounds. CRC Press, Boca Raton
Hayes JD, Flanagan JU, Jowsey IR (2005) Glutathione transferases. Annu Rev Pharmacol Toxicol 45: 51–88
Krynetski EY, Evans WE (1999) Pharmacogenetics as a molecular basis for individualized drug therapy: The thiopurine S-methyltransferase paradigm. Pharm Res 16: 342–349
Evans DA (1989) N-acetyltransferase. Pharmacol Ther 42: 157–234
Meisel P (2002) Arylamine N-acetyltransferases and drug response. Pharmacogenomics 3: 349–366
Arias IM, Jakoby WB (1976) Glutathione: Metabolism and Function. Raven Press, New York
Guengerich FP (2003) Cytochrome P450 oxidations in the generation of reactive electrophiles: The role of biotransformation and bioactivation in toxicity 85 Epoxidation and related reactions. Arch Biochem Biophys 409: 59–71
Ketterer B, Meyer DJ, Clark AG (1988) Soluble glutathione transferase isoenzymes. In: H Sies, B Ketterer (eds): Glutathione Conjugation: Mechanisms and Biological Significance. Academic Press, New York, 73–135
Morgenstern R, Lundqvist G, Andersson G, Balk L, DePierre JW (1984) The distribution of microsomal glutathione transferase among different organelles, different organs, and different organisms. Biochem Pharmacol 33: 3609–3614
Caldwell J, Jakoby WB (1983) Biological Basis of Detoxification. Academic Press, New York
Anders MW (2004) Glutathione-dependent bioactivation of haloalkanes and haloalkenes. Drug Metab Rev 36: 583–594
Bessems JG, Vermeulen NP (2001) Paracetamol (acetaminophen)-induced toxicity: Molecular and biochemical mechanisms, analogues and protective approaches. Crit Rev Toxicol 31: 55–138
Genter StClair MB, Amarnath V, Moody MA, Anthony DC, Anderson CW, Graham DG (1988) Pyrrole oxidation and protein cross-linking as necessary steps in the development of g-diketone neuropathy. Chem Res Toxicol 1: 179–185
Liebler DC, Guengerich FP (1983) Olefin oxidation by cytochrome P450: Evidence for group migration in catalytic intermediates formed with vinylidene chloride and trans-1-phenyl-1-butene. Biochemistry 22: 5482–5489
Pohl LR, Branchflower RV, Highet RJ, Martin JL, Nunn DS, Monks TJ, George JW, Hinson JA (1981) The formation of diglutathionyl dithiocarbonate as a metabolite of chloroform, bromotrichloromethane, and carbon tetrachloride. Drug Metab Dispos 9: 334–339
Anders MW, Dekant W (1994) Conjugation-Dependent Carcinogenicity and Toxicity of Foreign Compounds. Academic Press, New York
Anders MW, Dekant W, Vamvakas S (1992) Glutathione-dependent toxicity. Xenobiotica 22: 1135–1145
Dekant W, Vamvakas S, Anders MW (1992) The kidney as a target organ for xenobiotics bioactivated by glutathione conjugation. In: W Dekant, HG Neumann (eds): Tissue Specific Toxicity: Biochemical Mechanisms. Academic Press, New York, 163–194
Monks TJ, Anders MW, Dekant W, Stevens JL, Lau SS, van Bladeren PJ (1990) Glutathione conjugate mediated toxicities. Toxicol Appl Pharmacol 106: 1–19
Aust SD, Chignell CF, Bray TM, Kalyanaraman B, Mason RP (1993) Free radicals in toxicology. Toxicol Appl Pharmacol 120: 168–178
Goldstein BD, Czerniecki B, Witz G (1989) The role of free radicals in tumor promotion. Environ Health Perspect 81: 55–57
Goldstein BD, Witz G. (1990) Free radicals and carcinogenesis. Free Radic Res Commun 11: 3–10
Kehrer JP, Mossman BT, Sevanian A, Trush MA, Smith MT (1988) Free radical mechanisms in chemical pathogenesis. Toxicol Appl Pharmacol 95: 349–362
Cerutti PA, Trump BF (1991) Inflammation and oxidative stress in carcinogenesis. Cancer Cell 3: 1–7
Chacon E, Acosta D (1991) Mitochondrial regulation of superoxide by Ca2+: An alternate mechanism for the cardiotoxicity of doxorubicin. Toxicol Appl Pharmacol 107: 117–128
Burdon RH, Gill V, Rice-Evans C (1990) Oxidative stress and tumour cell proliferation. Free Radic Res Commun 11: 65–76
Pero RW, Roush GC, Markowitz MM, Miller DG (1990) Oxidative stress, DNA repair, and cancer susceptibility. Cancer Detect Prev 14: 551–561
Jakoby WB, Ziegler DM (1990) The enzymes of detoxication. J Biol Chem 265: 20715–20719
Sies H (1989) Zur Biochemie der Thiolgruppe: Bedeutung des Glutathions. Naturwissenschaften 76: 57–64
Ziegler DM (1980) Microsomal flavin-containing monooxygenase: Oxygenation of nucleophilic nitrogen and sulfur compounds. In: WB Jacoby (ed.): Enzymic Basis of Detoxification, vol 1. Academic Press, New York, 201–227
Boyland E, Chasseaud LF (1969) Role of glutathione and glutathione S-transferases in mercapturic acid biosynthesis. Adv Enzymol 32: 173–177
James RC, Harbison RD. (1982) Hepatic glutathione and hepatotoxicity. Biochem. Pharmacol. 31: 1829–1835
Chung FL, Pan J, Choudhury S, Roy R, Hu W, Tang MS (2003) Formation of trans-4-hydroxy-2-nonenal-and other enal-derived cyclic DNA adducts from omega-3 and omega-6 polyunsaturated fatty acids and their roles in DNA repair and human p53 gene mutation. Mutat Res 531: 25–36
West JD, Marnett LJ (2006) Endogenous reactive intermediates as modulators of cell signaling and cell death. Chem Res Toxicol 19: 173–194
McLellan LI, Wolf CR, Hayes JD (1989) Human microsomal glutathione S-transferase. Its involvement in the conjugation of hexachlorobuta-1,3-diene with glutathione. Biochem J 258: 87–93
Hinson JA, Roberts DW (1992) Role of covalent and noncovalent interactions in cell toxicity: Effects on proteins. Annu Rev Pharmacol Toxicol 32: 471–510
Nelson SD, Pearson PG (1990) Covalent and noncovalent interactions in acute lethal cell injury caused by chemicals. Annu Rev Pharmacol Toxicol 30: 169–195
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2009 Birkhäuser Verlag/Switzerland
About this chapter
Cite this chapter
Dekant, W. (2009). The role of biotransformation and bioactivation in toxicity. In: Luch, A. (eds) Molecular, Clinical and Environmental Toxicology. Experientia Supplementum, vol 99. Birkhäuser Basel. https://doi.org/10.1007/978-3-7643-8336-7_3
Download citation
DOI: https://doi.org/10.1007/978-3-7643-8336-7_3
Publisher Name: Birkhäuser Basel
Print ISBN: 978-3-7643-8335-0
Online ISBN: 978-3-7643-8336-7
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)