Other Data Relevant to an Evaluation of Carcinogenicity and Its Mechanisms
pp1005-1080-Section 4.qxd 30/04/2004 11:03 Page 1005 4. Other Data Relevant to an Evaluation of Carcinogenicity and its Mechanisms 4.1 Absorption, distribution, metabolism and excretion 4.1.1 Humans The Working Group attempted to provide extensive coverage of the published lite- rature since 1985, in some cases referring to recent reviews. (a) Introduction Most carcinogens are enzymatically transformed to a series of metabolites as the exposed organism attempts to convert them to forms that are more readily excreted. The initial steps are usually carried out by cytochrome P450 (P450) enzymes that oxygenate the substrate (Guengerich, 1997). Other enzymes such as lipoxygenases, cyclooxyge- nases, myeloperoxidase and monoamine oxidases may also be involved, but less com- monly. If the oxygenated intermediates formed in these initial reactions are electrophilic, they may react with DNA or other macromolecules to form covalent binding products known as adducts. This process is called metabolic activation. Alternatively, these meta- bolites may undergo further transformations catalysed by glutathione S-transferases, uri- dine-5′-diphosphate (UDP)-glucuronosyltransferases, epoxide hydrolase (EH), N-acetyl- transferases (NATs) (Kadlubar & Beland, 1985), sulfotransferases and other enzymes (Armstrong, 1997; Burchell et al., 1997; Duffel, 1997). Such reactions frequently, but not always, result in detoxification. Figure 4.1 presents an overview of the metabolism of the six tobacco smoke carci- nogens for which the formation of DNA adducts has been demonstrated in human tissues, namely, benzo[a]pyrene (IARC, 1983a, 1987), 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1- butanone (NNK) (IARC, 1985a; Hecht et al., 1994), N-nitrosodimethylamine (NDMA) (IARC, 1978a; Shuker & Bartsch, 1994), N′-nitrosonornicotine (NNN) (IARC, 1985b; Hecht et al., 1994), ethylene oxide (IARC, 1994a), and 4-aminobiphenyl (4-ABP) (IARC, 1972; Kadlubar, 1994).
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