Abstract
Foreign compounds to which humans are exposed undergo metabolic conversion mediated by metabolizing enzymes before they are eliminated from the body. Phase I activation enzymes catalyze oxidation, hydrolysis, and reduction reactions. The functionalized compounds then proceed with further reactions catalyzed by phase II detoxification enzymes, which generally convert functionalized foreign compounds into less reactive and water-soluble metabolites, thus facilitating their elimination from the organism. Advances in this area of research have revealed that many metabolizing enzymes exhibit genetic polymorphisms which play a crucial role in individual variations in response to foreign compound-mediated effects. Investigations of individual responsiveness to drugs or certain chemicals have shown considerable deviations, in part due to variations in the expressions of foreign compound metabolizing enzymes.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Bibliography
Alvarez-Diez TM, Zheng J (2004) Mechanism-based inactivation of cytochrome P450 3A4 by 4-ipomeanol. Chem Res Toxicol 17:150–157
Archer MC (1981) Reactive intermediates from nitrosamines. Adv Exp Med Biol 136:1027–1035
Baer BR, Rettie AE, Henne KR (2005) Bioactivation of 4-ipomeanol by CYP4B1: adduct characterization and evidence for an enedial intermediate. Chem Res Toxicol 18:855–864
Baum M, Amin S, Guengerich FP, Hecht SS et al (2001) Metabolic activation of benzo[c]phenanthrene by cytochrome P450 enzymes in human liver and lung. Chem Res Toxicol 14:686–693
Boocock DJ, Maggs JL, Brown K et al (2000) Major inter-species differences in the rates of O-sulphonation and O-glucuronylation of alpha-hydroxytamoxifen in vitro: a metabolic disparity protecting human liver from the formation of tamoxifen-DNA adducts. Carcinogenesis 21:1851–1858
Czerwinski M, McLemore TL, Philpot RM et al (1991) Metabolic activation of 4-ipomeanol by complementary DNA-expressed human cytochromes P-450: evidence for species-specific metabolism. Cancer Res 51:4636–4638
Falzon M, McMahon JB, Schuller HM et al (1986) Metabolic activation and cytotoxicity of 4-Ipomeanol in human non-small cell lung cancer lines. Cancer Res 46:3484–3489
Ilic Z, Crawford D, Vakharia D et al (2010) Glutathione-S-transferase A3 knockout mice are sensitive to acute cytotoxic and genotoxic effects of aflatoxin B1. Toxicol Appl Pharmacol 242:241–246
Jowsey IR, Jiang Q, Itoh K et al (2003) Expression of the aflatoxin B1-8,9-epoxide-metabolizing murine glutathione S-transferase A3 subunit is regulated by the Nrf2transcription factor through an antioxidant response element. Mol Pharmacol 64:1018–1028
Kato S, Shields PG, Caporaso NE et al (1994) Analysis of cytochrome P450 2E1 genetic polymorphisms in relation to human lung cancer. Cancer Epidemiol Biomarkers Prev 3:515–518
Kim SY, Laxmi YR, Suzuki N et al (2005) Formation of tamoxifen-DNA adducts via O-sulfonation, not O-acetylation, of alpha-hydroxytamoxifen in rat and human livers. Drug Metab Dispos 33:1673–1678
Kiss I, Sándor J, Pajkos G, Bogner B et al (2000) Colorectal cancer risk in relation to genetic polymorphism of cytochrome P450 1A1, 2E1, and glutathione-S-transferase M1 enzymes. Anticancer Res 20:519–522
Kondraganti SR, Fernandez-Salguero P et al (2003) Polycyclic aromatic hydrocarbon-inducible DNA adducts: evidence by 32P-postlabeling and use of knockout mice for Ah receptor-independent mechanisms of metabolic activation in vivo. Int J Cancer 103:5–11
Li TK (2000) Pharmacogenetics of responses to alcohol and genes that influence alcohol drinking. J Stud Alcohol 61:5–12
Neafsey P, Ginsberg G, Hattis D et al (2009) Genetic polymorphism in CYP2E1: population distribution of CYP2E1 activity. J Toxicol Environ Health B Crit Rev 12:362–388
Nimura Y, Yokoyama S, Fujimori M et al (1997) Genotyping of the CYP1A1 and GSTM1 genes in esophageal carcinoma patients with special reference to smoking. Cancer 80:852–857
Oscarson M (2001) Genetic polymorphisms in the cytochrome P450 2A6 (CYP2A6) gene: implications for interindividual differences in nicotine metabolism. Drug Metab Dispos 29:91–95
Oscarson M, McLellan RA, Gullstén H et al (1999) Identification and characterisation of novel polymorphisms in the CYP2A locus: implications for nicotine metabolism. FEBS Lett 460:321–327
Palma S, Cornetts T, Padua L et al (2007) Influence of glutathione S-transferase polymorphisms on genotoxic effects induced by tobacco smoke. Mutat Res 633:1–12
Phillips DH, Carmichael PL, Hewer A et al (1996) Activation of tamoxifen and its metabolite alpha-hydroxytamoxifen to DNA-binding products: comparisons between human, rat and mouse hepatocytes. Carcinogenesis 17:89–94
Rothman N, Shields PG, Poirier MC et al (1995) The impact of glutathione S-transferase M1 and cytochrome P450 1A1 genotypes on white-blood-cell polycyclic aromatic hydrocarbon-DNA adduct levels in humans. Mol Carcinog 14:63–68
Sgambato A, Campisi B, Zupa A et al (2002) Glutathione S-transferase (GST) polymorphisms as risk factors for cancer in a highly homogeneous population from southern Italy. Anticancer Res 22:3647–3652
Shupe T, Sell S (2004) Low hepatic glutathione S-transferase and increased hepatic DNA adduction contribute to increased tumorigenicity of aflatoxin B1 in newborn and partially hepatectomized mice. Toxicol Lett 148:1–9
Wang J, Pitarque M, Ingelman-Sundberg M (2005) 3′-UTR polymorphism in the human CYP2A6 gene affects mRNA stability and enzyme expression. Biochem Biophys Res Commun 340:491–497
Watanabe J, Hayashi S, Kawajiri K (1994) Different regulation and expression of the human CYP2E1gene due to the RsaI polymorphism in the 5′-flanking region. J Biochem 116:321–326
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
Copyright information
© 2012 Springer Science+Business Media, LLC
About this chapter
Cite this chapter
Chen, CH. (2012). Genetic Variations in Metabolizing Enzymes. In: Activation and Detoxification Enzymes. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-1049-2_8
Download citation
DOI: https://doi.org/10.1007/978-1-4614-1049-2_8
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4614-1048-5
Online ISBN: 978-1-4614-1049-2
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)