The Role of Cytochrome P450 Enzymes in Carcinogen Metabolism: Lessons Learned From Studies With Benzo[a]pyrene and Aristolochic Acid
Abstrakt
This chapter summarizes the latest data increasing our knowledge on a function of cytochrome P450 (P450) enzymes in metabolism of several carcinogens and on the mechanisms of the reaction cycle catalyzed by the P450-monooxygenase system. Particularly it describes the P450-dependent metabolism, toxicity, and carcinogenicity of two human environmental carcinogens, benzo[a]pyrene (BP) and aristolochic acid I (AAI).
This chapter focuses on studies that have specifically investigated the role of P450 enzymes in the bioactivation and detoxification of BP and AAI, and the lessons learned from these studies in examining the potential role of P450-mediated metabolism for other known or putative human environmental carcinogens. P450 enzymes play a key role both in metabolic activation of these human carcinogens to the reactive intermediates forming DNA adducts, and in their detoxification to metabolites that are excreted.
While BaP is oxidatively metabolized (activated or detoxified) by P450s, AAI can be metabolized both oxidatively (to its detoxification metabolite aristolochic acid Ia [AAIa]) and reductively (to be activated to DNA-binding metabolites). Concerning the mechanisms of reactions catalyzed by the microsomal P450 monooxygenase system reviewed in this chapter, it is demonstrated that besides NADPH:cytochrome P450 oxidoreductase (POR), the system consisting of microsomal NADPH:cytochrome b5 reductase together with its substrate cytochrome b5 and cofactor NADH can function as a donor of electrons both for the first and the second reduction of at least some of P450 enzymes in their reaction cycle.
These findings indicate that the old myth, the generally accepted mechanism on the exclusivity of the POR/NADPH system for reduction of several P450s, should be revised.