Metabolism of Benzo[a]anthracene to Its Tumorigenic 3,4-Dihydrodiol

The weak carcinogenicity of benzo[a]anthracene may be due to either low amounts of the tumorigenic 3,4-dihydrodiol formed or poor conversion of this diol to the bay-region diol epoxides, i.e., benzo[a]anthracene 3,4-diol-1,2-epoxides. We have investigated the metabolism of benzo[a]anthracene with rat liver microsomes and a highly purified monooxygenase system reconstituted with cytochrome P-448 to determine the relative amounts of the 3,4-dihydrodiol formed. With liver microsomes from induced and uninduced rats, as well as with the purified and reconstituted system in the presence of epoxide hydrase, benzo[a]anthracene was metabolized predominantly to its 5,6- and 8,9-dihydrodiols. Small but significant amounts of the 3,4- and 10,11-dihydrodiols were also detected by chromatographic methods and fluorescence spectrometry. Since only trace amounts of phenols were detected, the arene oxides of benzo[a]amthracene must be good substrates of epoxide hydrase. With the purified and reconstituted system in the absence of epoxide hydrase, only phenols and the K-region 5,6-oxide were found to be metabolites of benzo[a]-anthracene. Moreover, the extent of metabolism of benzo[a]anthracene was substantially reduced in the absence of epoxide hydrase, suggesting that phenolic metabolites are potent inhibitors. Strong inhibition of the metabolism of benzo[a]anthracene by synthetic 5- and 6-hydroxybenzo[a]anthracenes and by a mixture of phenolic metabolites was observed. ACKNOWLEDGMENTS The authors wish to thank Mrs. Janet Deyhle for her excellent help in the preparation of this manuscript.