Dihydrodiol epoxides carcinogenic initiation

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. 

Chrysene is a weak tumor initiator and is inactive as a complete carcinogen (38). The 1,2-dihydrodiol is more active as a mutagen than the 3,4- or the 5,6-dihydrodiols. The biological data support the hypothesis that the principal active metabolite of chrysene is the bay region anti-1,2-diol-3,4-epoxide (58). 

Initially, particular attention was focused on the epoxides of the so-called K region. As in the case of benzo [a] pyrene and certain other polycyclic aromatic hydrocarbons, these were more carcinogenic than the parent compound. The K region had attracted particular interest, as it is electronically the most reactive portion of the polycyclic aromatic hydrocarbon molecule. However, with other carcinogenic polycyclic aromatic hydrocarbons, this was not found to be the case. It now seems that the ultimate carcinogen is an epoxide of a dihydrodiol metabolite, where the epoxide is adjacent to the so-called bay region (Fig. 7.2). 

The primary toxic effect of concern for chrysene is carcinogenicity, which is most likely the result of the mutagenic activity of its metabolites, 1,2-dihydrodiol and l,2-diol-3,4-epoxide. The 1,2-dihydrodiol and the l,2-diol-3,4-epoxide have been shown to be mutagenic in vitro in bacterial and mammalian cells and have induced pulmonary adenomas when administered to newborn mice. In addition, the 1,2-dihydrodiol was active as a tumor initiating agent on mouse skin. DNA adducts in hamster cells resulting from a reaction of the DNA with l,2-diol-3,4-exp-oxide have also been detected. 

Figure 7.9 Another environmental carcinogen is benzo[a]pyrene (BaP). One site of metabolic attack is the terminal ring which is oxidized to form a 7,8-arene oxide. Epoxide hydrolase opens this to form a frans-7,8-dihydrodiol.The remaining C=C bond in the ring may also undergo oxidation to form an epoxide, with the oxidation directed to the same face as the allylic alcohol by coordination of the metabolizing enzyme. This epoxide is now on the opposite face as the benzylic hydroxyl group and is named BaP-frans-7,8-diol-anf/-9,10-epoxide.This is especially stable because it is adjacent to the sheltered bay region of the molecule. It can be opened by epoxide hydrolase to form a detoxified tetraol. Alternatively, DNA can open the epoxide to form a covalent adduct that is responsible for tumor initiation.

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