Complex Metabolic Activation Pathways of Polycyclic Aromatic Hydrocarbons: 3-Hydroxy-trans-7,8-Dihydroxy-7,8-Dihydrobenzo[a]Pyrene as a Proximate Mutagen of 3-Hydroxybenzo[a]Pyrene
3-Hydroxybenzo[a]pyrene (3-OH-BP) is a major metabolite of benzo[a]pyrene (BP) in various systems. Metabolites of 3-OH-BP, formed by liver enzymes, bind to DNA1,2 and are mutagenic3,4. However, the active species have not yet been identified. Administration of 3-OH-BP to rats results in the excretion of sulfate and glucuronic acid conjugates of 3-hydroxy-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (3-OH-BP-7,8-diol) (Fig. 1) as major metabolites in the bile5. The hydroxyl groups of this triol are structurally superimposable to those of 9-hydroxy-trans-1,2-dihydroxy-1,2-dihydrochrysene (9-hydroxychrysene-1,2-diol, Fig. 1), which is a metabolite of chrysene6,7 and a potent promutagen8,9. 9-Hydroxychrysene-1,2-diol is activated by mammalian enzymes to anti-chrysene-1,2-diol-3,4-oxide7, which is chemically more reactive, is more mutagenic in bacterial and mammalian cells and is more potent in the malignant transformation of C3H10T1/2 cells than is the simple bay-region diol-epoxide of chrysene8,9. Furthermore, after application of chrysene to mouse skin, a target organ for carcinogenicity, this triol-epoxide forms a major type of DNA-adduct7,10. The higher chemical reactivity and biological activity of 9-hydroxychrysene-1,2-diol-3,4-oxides as compared to the chrysene-1,2-diol-3,4-oxides may be explained, and were predicted, on electronic grounds11: the hydroxyl group may resonance-stabilize the bay-region carbonium ion that results from opening of the oxirane ring. Analogous resonance stabilization is expected to occur with the carbonium ions formed from 3-0H-BP-7,8-diol-9,10-oxides11. Therefore, it was of interest to investigate the novel, secondary BP metabolite, 3-OH-BP-7,8-diol, for mutagenity.
KeywordsPolycyclic Aromatic Hydrocarbon Mouse Skin High Chemical Reactivity Glucuronic Acid Conjugate Mutagenic Potency
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