4. Other Data Relevant to an Evaluation of Carcinogenicity and its Mechanisms

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, cyclooxygenases, myeloperoxidase and monoamine oxidases may also be involved, but less commonly. 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 metabolites may undergo further transformations catalysed by glutathione S-transferases, uridine-5′-diphosphate (UDP)-glucuronosyltransferases, epoxide hydrolase (EH), N-acetyltransferases (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 carcinogens 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)-1butanone (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). The major metabolic activation pathway of benzo[a]pyrene is conversion to a 7,8-diol-9,10-epoxide, which is highly carcinogenic and reacts with DNA to form adducts with the exocyclic N2 of guanine (Cooper et al., 1983). In competition with this process are detoxification pathways leading to phenols, diols and their conju-