Abstract
Benzo[a]pyrene (BP) 7,8-dihydrodiol is metabolized by the rat liver monooxygenase system to diastereomeric benzo[a]pyrene 7,8-diol 9,10-epoxides that are highly reactive, toxic, and mutagenic. One of the isomers of these diol epoxides is highly carcinogenic to newborn mice. Oxidative metabolism of (-)-benzo[a]pyrene 9,10-dihydrodiol has been investigated to see whether 9,10-diol 7,8-epoxides are formed in analogy to the metabolism of BP 7,8-dihydrodiol, and mutagenic activities of synthetic BP 9,10-diol 7,8-epoxides have been evaluated. Unlike BP 7,8-dihydrodiol, the (-)-9,10-dihydrodiol is metabolized primarily to a phenolic derivative rather than a diol epoxide. Chemical and spectral studies established that the phenolic hydroxyl group had been introduced at either position 1 or 3 of the 9,10-dihydrodiol. Weak inherent mutagenic activity of the synthetic 9,10-diol 7,8-epoxides and the very low degree of their metabolic formation explains why metabolic activation of BP 9,10-dihydrodiol in the presence of Salmonella typhimurium results in a weak mutagenic response compared with studies with the 7,8-dihydrodiol as substrate. Chronic application of 0.15 µmole of BP 9,10-dihydrodiol to the backs of C57BL/6J mice once every 2 weeks for 60 weeks failed to produce tumors, whereas the same treatment with BP resulted in a 97% incidence of tumors.
- Copyright © 1978 by Academic Press, Inc.
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