RT Journal Article
SR Electronic
T1 Metabolism of <em>trans</em>-9,10-Dihydroxy-9,10-dihydrobenzo[<em>a</em>]pyrene Occurs Primarily by Arylhydroxylation Rather than Formation of a Diol Epoxide
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 502
OP 513
VO 14
IS 3
A1 D. R. THAKKER
A1 H. YAGI
A1 R. E. LEHR
A1 W. LEVIN
A1 M. BUENING
A1 A. Y. H. LU
A1 R. L. CHANG
A1 A. W. WOOD
A1 A. H. CONNEY
A1 D. M. JERINA
YR 1978
UL http://molpharm.aspetjournals.org/content/14/3/502.abstract
AB 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.