Benzo pyrene diol epoxides metabolic activation

PAHs are ubiquitous environmental pollutants known to be mutagenic and carcinogenic in mammalian cells [131, 132]. PAHs require metabolic activation that results in diol epoxide formation via reactions that are catalyzed by epoxide hydrolase and the CYP450 family of enzymes [133], Diol epoxides are highly reactive, particularly toward purines in DNA, forming guanine and adenine adducts that exist as as and trans stereoisomers [134]. Transcription past adducts derived from diol epoxides of benzo[o]pyrene (benzo[a]pyrene diol expoxide (B[a]PDE)), benzo[c]phenanthrene (benzo[c]phenanthrene diol epoxide (B[c]PhDE)), and dibenzo[a,l]pyrene (dibenzo[o,l]pyrene diol epoxide (B[a,l]PDE)) has been studied. 

The reaction of metabolically generated polycyclic aromatic diol epoxides with DNA Ua vivo is believed to be an important and critical event in chemical carcinogenesis Cl,2). In recent years, much attention has been devoted to studies of diol epoxide-nucleic acid interactions in aqueous model systems. The most widely studied reactive intermediate is benzo(a)pyrene-7,8-diol-9,10-epoxide (BaPDE), which is the ultimate biologically active metabolite of the well known and ubiquitous environmental pollutant benzo(a)pyrene. There are four different stereoisomers of BaPDE (Figure 1) which are characterized by differences in biological activities, and reactivities with DNA (2-4). In this review, emphasis is placed on studies of reaction mechanisms of BPDE and related compounds with DNA, and the structures of the adducts formed. 

Sims, P. and P.L. Grover. 1981. Involvement of dihydrodiols and diol epoxides in the metabolic activation of polycyclic hydrocarbons other than benzo[a]pyrene. Pages 117-181 in H.V. Gelboin and P.O. Ts o (eds.). Polycyclic Hydrocarbons and Cancer. Vol. 3. Academic Press, New York. 

A. Metabolic activation of benzo(a)pyrene proceeds by a diol-epoxide. Nature (1974) 252 326-328. 

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.

The ultimate carcinogens arising from the metabolic activation of benzo(a)pyrene are stereoisomers of benzo(a)pyrene 7,8-diol-9,10-epoxide (Figure 7.3). These metabolites arise by prior formation of the 7,8 epoxide, which gives rise to the 7,8-dihydrodiol... 

Sims, P., P.L. Grover, A. Swaisland, K. Pal, and A. Hewer. Metabolic activation of benzo(a)pyrene proceeds by a diol-epoxide. Nature 252 326-328,... 

Figure 24.11. Metabolic activation of benzo[a]pyrene to the ultimate carcinogenic species. Benzo[a]pyrene is metabolized by cytochromes P-450 and epoxide hydrolase to form the ultimate carcinogen, (+)benzo[a]pyrene-7,8-diol-9,10 epoxide-2. (Adapted from Conney, A. H. Cancer Res. 42, 4875,1982.)...

Continued studies from several laboratories of the binding, mutagenicity and tumorigenicity of benzo [a] pyrene and its derivatives led to the identification of (+)-(7R,8S)-dihydroxy-(9S,10R)-epoxy-7,8,9,10-tetrahydrobenzo[aJpyrene (a diol epoxide-2 diastereomer) as the principal metabolite responsible for the carcinogenic activity of benzo[a]pyrene. Only one of the four metabolically possible isomers of the 7,8-diol-9,10-epoxide was found to have high tumorigenic activity... 

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