Benzo pyrene dihydrodiols

Fig. 10.13. Metabolism of benzo[ ]pyrene (10.34). Shown are stereoselective formation of three isomeric epoxides, EH-catalyzed, stereoselective hydration to the dihydrodiols 10.35, 10.36, and 10.37, and, finally, 9,10-epoxidation of 10.36 to the bay-region diol epoxide 10.38. The latter exists as...

BenzoWpyrene Sdenastrum capricomutum. Benzo[< ]pyrene r r-4,5-d ihydrod iol, benzo[< ]pyrene cis-1,8-d ihydrod iol, benzoMpyrene c/j-9,10-d ihydrod iol, benzoMpyrene cis-l 1,12-dihydrodiol. Cody et al. (1984), Lindquist Warshawsky (1985a,b), Warshawsky et al. (1988, 1990). 

Syn dihydrodiol epoxide adducts formed in mouse skin treated with benzo[ ]pyrene constitute only about 12% of the total binding (36) and dihydrodiol epoxide deoxyadenosine adducts account for even less (2 to 3%) of the total (37,38). DMBA is approximately 20 times more potent a carcinogen than BP and this difference cannot be explained by the 2- to 4-fold difference in overall binding to DNA by these two carcinogens in mouse skin (35). Thus, these more subtle differences in DNA reaction products, i.e. the difference in reaction of syn-stereoisomer with DNA or in the modification of deoxyadenosine residues, might account for the greater tumor-initiating potential of DMBA. 

Cavalieri EL, Higginbotham S, Ramakrishna N VS, et al. 1991. Comparative dose-response tumorigenicity studies of dibenzo(a)pyrene versus 7,12-dimethylbenz(a)anthracene, benzo(a)pyrene and two dibenzo(a)pyrene dihydrodiols in mouse skin and rat mammary gland. Carcinogenesis 12(10) 1939-1944. 

It is postulated that this ultimate carcinogen reacts covalently with nucleic acids, producing nucleic acid adducts. It has been demonstrated that benzo[a]pyrene reacts covalently with nucleic acids in vitro, provided that the microsomal enzyme systems necessary for activation are present, and also in whole cell systems. The 7,8-dihydrodiol metabolite of benzo[ ]pyrene binds more extensively to DNA after microsomal enzyme activation than does benzo[a]pyrene or other benzo[a]pyrene metabolites, and the nucleoside adducts formed from the 7,8-dihydrodiol of benzo[tf]pyrene are similar to those obtained from cells in culture exposed to benzo[ ]pyrene itself. Furthermore, the synthetic 7,8-diol-9,10-epoxides of benzo[a]pyrene are highly mutagenic in mammalian as well as in bacterial cells. 

Cheng, S.C., Hilton, B.D., Roman, J.M., and Dipple, A. (1989) DNA adducts from carcinogenic and noncarcinogenic enantiomers of benzo[a]pyrene dihydrodiol epoxide. Chem. Res. Toxicol., 2, 334-340. 

The aryl hydroxylase of Saccharomyces cerevisiae that transforms benzo[a]pyrene to the 3- and 9-hydroxy compounds, and the 7,8-dihydrodiol (King et al. 1984). 

A cytochrome P450 has been purified from Saccharomyces cerevisiae that has benzo[a]pyrene hydroxylase activity (King et al. 1984), and metabolizes benzo[fl]pyrene to 3- and 9-hydroxybenzo[fl]pyrene and benzo[fl]pyrene-7,8-dihydrodiol (Wiseman and Woods 1979). The transformation of PAHs by Candida Upolytica produced predominantly monohydroxyl-ated products naphth-l-ol from naphthalene, 4-hydroxybiphenyl from biphenyl and 3- and 9-hydroxybenzo[fl]pyrene from benzo[fl]pyrene (Cerniglia and Crow 1981). The transformation of phenanthrene was demonstrated in a number of yeasts isolated from littoral sediments and of these, Trichosporumpenicillatum was the most active. In contrast, biotransformation of benz[fl]anthracene by Candida krusei and Rhodotorula minuta was much slower (MacGillivray and Shiaris 1993). 

Figure 2. 7-Methylbenz[a]anthracene and benzo[a]pyrene indicating those regions defined as bay regions and the structures of the corresponding bay region dihydrodiol epoxides.

Figure 4. The bay region dihydrodiol epoxide route of metabolism of benzo[a]pyrene.

Table I. Optical Purity of the Dihydrodiol Metabolites Formed in the Metabolism of Benzo[a]pyrene by Liver Microsomes from Untreated, Phenobarbital (PB)-, 3-Methylcholanthrene (3MC)-, and Polychlorinated Biphenyls (PCBs, Aroclor 1254)-Treated Rats...

Methods for the synthesis of the biologically active dihydrodiol and diol epoxide metabolites of both carcinogenic and noncarcinogenic polycyclic aromatic hydrocarbons are reviewed. Four general synthetic routes to the trans-dihydrodiol precursors of the bay region anti and syn diol epoxide derivatives have been developed. Syntheses of the oxidized metabolites of the following hydrocarbons via these methods are described benzo(a)pyrene, benz(a)anthracene, benzo-(e)pyrene, dibenz(a,h)anthracene, triphenylene, phen-anthrene, anthracene, chrysene, benzo(c)phenanthrene, dibenzo(a,i)pyrene, dibenzo(a,h)pyrene, 7-methyl-benz(a)anthracene, 7,12-dimethylbenz(a)anthracene, 3-methylcholanthrene, 5-methylchrysene, fluoranthene, benzo(b)fluoranthene, benzo(j)fluoranthene, benzo(k)-fluoranthene, and dibenzo(a,e)fluoranthene. 

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. 

Bowden, G.T., Hsu, I.C., and Harris, C.C. (1979). The effect of caffeine on cytotoxicity, mutagenesis and sister chromatid exchanges in Chinese hamster cells treated with dihydrodiol epoxide derivatives of benzo(a)pyrene. Mutation Res. 63 361-370. 

Trichloroethylene Vinyl chloride CYP3A4 Acetaminophen Aflatoxin Bi and Gi 6-Aminochrysene Benzo[a]pyrene 7,8-dihydrodiol Cyclophosphamide Ifosphamide 1-Nitropyrene Sterigmatocystin Senecionine... 

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