Diol epoxides from polycyclic hydrocarbons

These findings indicate that PGH synthase in the presence of arachidonate can catalyze the terminal activation step in BP carcinogenesis and that the reaction may be general for dihydrodiol metabolites of polycyclic hydrocarbons. Guthrie et. al. have shown that PGH synthase catalyzes the activation of chrysene and benzanthracene dihydrodiols to potent mutagens (33). As in the case with BP, only the dihydrodiol that is a precursor to bay region diol epoxides is activated. We have recently shown that 3,4-dihydroxy-3,4-dihydro-benzo(a)anthracene is oxidized by PGH synthase to tetrahydrotetraols derived from the anti-diol epoxide (Equation 4) (34). 

A potentially powerful probe for sorting out the contribution of hydroperoxide-dependent and mixed-function oxidase-dependent polycyclic hydrocarbon oxidation is stereochemistry. Figure 9 summarizes the stereochemical differences in epoxidation of ( )-BP-7,8-dihydrodiol by hydroperoxide-dependent and mixed-function oxidase-dependent pathways (31,55,56). The (-)-enantiomer of BP-7,8-dihydrodiol is converted primarily to the (+)-anti-diol epoxide by both pathways whereas the (+)-enantiomer of BP-7,8-dihydrodiol is converted primarily to the (-)-anti-diol epoxide by hydroperoxide-dependent oxidation and to the (+)-syn-diol epoxide by mixed-function oxidases. The stereochemical course of oxidation by cytochrome P-450 isoenzymes was first elucidated for the methycholanthrene-inducible form but we have detected the same stereochemical profile using rat liver microsomes from control, phenobarbital-, or methyl-cholanthrene-induced animals (32). The only difference between the microsomal preparations is the rate of oxidation. 

Sayer JM, Whalen DL, Jerina DM. Chemical strategies for the inactivation of bay-region diol-epoxides, ultimate carcinogens derived from polycyclic aromatic hydrocarbons. Drug Metab Rev 1989 20 155. 

Figure 24.13. Examples of bay region diol epoxide ultimate carcinogenic species of various polycyclic aromatic hydrocarbons (PAHs). Polycyclic aromatic hydrocarbons are metabolized to highly electrophihc bay region diol epoxides that are considered to be the ultimate carcinogenic species. (Adapted from Conney, A. H. Cancer Res. 42, 4875, 1982.)...

Lodovici, M., Akpan, V., Giovannini, L., MigUani, F. Dolara, P. (1998). Benzo[n]pyrene diol-epoxide DNA adducts and levels of polycyclic aromatic hydrocarbons in autoptic samples from human lungs. Chemico-Biological Interactions, 116, 199-212. 

Haugen A. Becher G, Benestad C, et al. 1986. Determination of polycyclic aromatic hydrocarbons in the urine. benzo(a)pyrene diol epoxide-DNA adducts in lymphocyte DNA, and antibodies to the adducts in sera from coke oven workers exposed to measured amount of polycyclic aromatic hydrocarbons in the work atmosphere. Cancer Res 46 4178-4183. 

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