Central role of radical cations in metabolic activation of polycyclic aromatic hydrocarbons

Abstract

1. Development of the chemistry of polycyclic aromatic hydrocarbon (PAH) radical cations has provided evidence that these intermediates play a major role in the metabolism of PAHs by P450 and in their binding to DNA.

2. Fluoro substitution of benzo[a]pyrene (BP) represents a suitable probe for studying mechanisms of oxygen transfer in the P450-catalysed formation of quinones and phenols from BP. Formation of BP-1,6-, -3,6- and -6,12-dione from the metabolism of 6-fluoroBP (6-FBP) is mediated by the intermediate 6-FBP⁺. Similarly, metabolism of 1-FBP and 3-FBP by rat liver microsomes produces BP-1,6-dione and BP-3,6-dione respectively. These results demonstrate that formation of quinones and phenols occurs via an initial electron transfer from BP to P450 and subsequent transfer of oxygen from the iron-oxo complex of P450 to BP.

3. Radical cations also play a major role in the formation of DNA adducts by the potent carcinogens 7,12-dimethylbenz[a]anthracene (DMBA), BP and dibenzo[a, l]pyrene (DB[a, l]P). In the binding of BP both in vitro and in vivo, 80% of the adducts are formed by one-electron oxidation, namely, 8-(BP-6-yl)guanine (BP-6-C8Gua), BP-6-N7Gua and BP-6-N7adenine (Ade), and are lost from the DNA by depurination. For DB[a, l]P, depurinating adducts formed from the radical cation, DB[a, l]P-10-C8Gua, DB[a, l]P-10-N7Gua, DB[a, l]P-10-N7Ade, and DB[a, l]P-10-N3Ade comprise 50% of the total DNA adducts. For DMBA, 99% of the adducts are depurinating adducts formed from the radical cation, 7-CH₃BA-12-CH₂-N7Gua and 7-CH₃BA-12-CH₂-N7Ade.

4. In summary, radical cations of PAHs play a major role in both the metabolism and metabolic activation leading to formation of DNA adducts that are critical in the mechanism of tumour initiation.