Diol epoxides mutagen

G.A. Reed, M.J. Ryan, K.S. Adams, Sulfite enhancement of diol epoxide mutagenicity the role of altered glutathione metabolism. Carcinogenesis 11 (9) (1990) 1635—1639. 

Recent advances in PAH carcinogenesis research over the past decade have led to identification of diol epoxide metabolites as the principal active forms of the PAH investigated to date Q,2). Benzo-(a)pyrene (BP) has been most intensively investigated, and it has been demonstrated that a diol epoxide metabolite anti-BPDE is the active intermediate which binds covalently to DNA in human and other mammalian tissues 0,4). Anti-BPDE was also demonstrated to be a powerful mutagen in both bacterial and mammalian cells (15) These findings stimulated an outpouring of research directed towards elucidation of the molecular mechanism of PAH carcinogenesis. 

Mutagenicity of diol epoxides. The intrinsic mutagenicities of ten diol epoxides-1 and twelve diol epoxides-2 toward S. typhimurium strain TA 100 and Chinese hamster V79 cells have been determined (14,28,29). For diol epoxides-1, the logarithms of the relative mutagenicities vs. the calculated values of AE(je oc/8 are given in... 

Several observations can be made about the mutagenicity values. First, the highly-hindred BcPh bay-region diol epoxides exhibit mutagenicities far in excess of what might have been anticipated based upon their calculated AEd values, and the basis... 

Figure 5. Plots of log rel. mutagenicity toward Sj typhimurium TA 100 and Chinese hamster V79 cells versus AE eioc/3 for PAH diol epoxides-1. Numbers refer to the position of the epoxide the epoxide is at a bay region if the number is not given. (Adapted from Refs. 14, 28, and 29.)...

The mutagenicities of the bay region diol epoxides derived from BA, BaAcr and BcAcr toward S. typhimurium strain TA 100 (similar results are obtained in strain TA 98) and Chinese hamster V79 cells... 

Figure 7. Mutagenicities of BA, BaAcr, and BcAcr bay region diol epoxides in S. typhimurium TA 100 and Chinese hamster V79 cells. (Adapted from Ref. 29).

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). 

Although dihydrodiols are readily excreted, in general, it is now clear that diol-epoxides are formed and that these highly reactive intermediates may be important in mutagenicity, tumorigenesis, toxicity, and birth defects. Diols can therefore imdergo further Goxygenations (Thble 5.3). 

Rodriguez H, Loechler EL. 1993. Mutational specificity of the (+) - anti-diol epoxide of benzo [a] pyrine in a supF gene of an Escherichia coli plasmid DNA sequence context influences hotspots, mutagenic specificity and the extent of SOS enhancements of mutagenesis. Carcinogenesis 14(3) 373-383. 

Although a number of the epoxides and diol epoxides are mutagenic, the 7,8-dihydrodiol 9,10-oxide, shown in Figure 7.2, is believed to be the ultimate carcinogen. It should be noted that there are several possible diastereoisomers of this metabolite, but as the action of epoxide hydrolase yields a trans dihydrodiol and the epoxide ring produced by the cytochrome P-450 may be cis or trans, there are two diastereoisomers produced metabolically. Thus, benzo(a)pyrene... 

Figure 7.2 The metabolic activation of benzo[a]pyrene by cytochrome P-450 1A1 to a diol epoxide metabolite, a mutagen. This is believed to be the ultimate carcinogenic metabolite. Other routes of metabolism also catalyzed by cytochrome P-450 give rise to the 9,10, and 4,5 oxides and subsequent metabolites namely phenols, diols, and glutathione conjugates. The reactive site (carbon atom) on the metabolite is indicated.

Adler, I.-D., Kliesch, U., Nylund, L. Peltonen, K. (1997) In vitro and in vivo mutagenicity of the butadiene metabolites butadiene diol epoxide, butadiene monoepoxide and diepoxybutane. Mutagenesis, 12, 339-345... 

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