Mutagenicity of the dihydrodiols and bay-region diol-epoxides of benzo(c)phenanthrene in bacterial and mammalian cells.

Abstract

The mutagenic activity of benzo( c )phenanthrene and some of its known and potential metabolites was evaluated in bacterial and mammalian cells either in the presence or absence of a metabolic activation system. trans -3,4-Dihydroxy-3,4-dihydrobenzo( c )phenanthrene [benzo( c )phenanthrene 3,4-dihydrodiol] was metabolized by a cytochrome P-450-dependent monooxygenase system to products which were severalfold more mutagenic to strains TA98 and TA100 of Salmonella typhimurium than were the metabolic products formed from benzo( c )phenanthrene or its 1,2- or 5,6-dihydrodiols. When the double bond in the 1,2-position of benzo( c )phenanthrene 3,4-dihydrodiol was replaced by a single bond, the resulting tetrahydrodiol could not be metabolically activated, suggesting that one or both diastereomeric bay-region diol-epoxides was the bioactivated metabolite of the 3,4-dihydrodiol of benzo( c )phenanthrene. Both of these bay-region diol-epoxide diastereomers were highly mutagenic in bacterial and mammalian cells and were very poor substrates for epoxide hydrolase. (±)-3α,4β-Dihydroxy-1β,2β-epoxy-1,2,3,4-tetrahydrobenzo( c )phenanthrene (diol-epoxide 1), in which the epoxide oxygen and the benzylic hydroxyl group are cis , induced histidine prototrophy in strains TA98 and TA100 of S. typhimurium at a mutation rate of 1000 and 2700 revertants/nmol, respectively. A 1 µm concentration of this diol-epoxide killed one-half of the treated Chinese hamster V79 cells and induced mutations in the surviving cells at a rate of 100 8-azaguanine-resistant cells/105 surviving cells. (±)-3α,4β-Dihydroxy-1α,2α-epoxy-1,2,3,4-tetrahydrobenzo( c )phenanthrene (diol-epoxide 2), in which the epoxide oxygen and the benzylic hydroxyl group are trans , had from 80 to 250% of the mutagenic and cytotoxic activity of its diastereomer. These data strongly suggest that in species capable of the appropriate metabolic transformations of benzo( c )phenanthrene, the 3,4-dihydrodiol and one or both of its diastereomeric bay-region diol-epoxides are proximate and ultimate carcinogens, respectively.