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

The mutagenic activity of benzo(c)phenanthrene and some of its known and potential metabolites was evaluated in bac terial and mammalian cells either in the presence or absence of a metabolic activation system. trans-3,4-Dihydroxy-3,4-di hydrobenzo(c)phenanthrene [benzo(c)phenanthrene 3,4-di hydrodiol] 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 1,2or 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 diob-epoxide diastereomers were highly mutagenic in bacterial and mam malian cells and were very poor substrates for epoxide hydro base. (±)-3a,4,8-Dihydroxy-1/J,2,0-epoxy-1,2,3,4-tetrahydro benzo(c)phenanthrene (diol-epoxide 1), in which the epoxide oxygen and the benzylic hydroxyb group are cis, induced histidine prototrophy in strains TA98 and TA100 of S. typhi murium at a mutation rate of I 000 and 2700 revertants/nmob, respectively. A I @tMconcentration 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 I 00 8-azaguanine resistantcells/1 0@surviving cells. (±)-3a,4f1-Dihydroxy-1a,2aepoxy-i ,2,3,4-tetrahydrobenzo(c)phenanthrene (diol-epoxide 2), in which the epoxide oxygen and the benzylic hydroxyb group are trans, had from 80 to 250% of the mutagenic and cytotoxic activity of its diastereomer. These data strongly sug gest 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.