Marked differences in the skin tumor-initiating activities of the optical enantiomers of the diastereomeric benzo(a)pyrene 7,8-diol-9,10-epoxides.

Abstract The abilities of the optically pure (+)- and (-)-enantiomers of the diastereomeric 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo( a )pyrenes derived from the enantiomeric trans -7,8-dihydrodiols to initiate skin tumors in mice were determined with a two-stage system of tumorigenesis. As a tumor initiator, (+)-7β,8α-dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydrobenzo( a )pyrene 2 was approximately 60% as active as was benzo( a )pyrene, whereas (-)-7α,8β-dihydroxy-9β,10β-epoxy-7,8,9,10-tetrahydrobenzo( a )pyrene 2 was about 2% as active as was benzo( a )pyrene. The racemic mixture of the above diol-epoxide, in which the 9,10-epoxide is trans to the 7-hydroxyl group, was 25% as active as was benzo( a )pyrene as a tumor initiator. (-)-7β,8α-Dihydroxy-9β,10β-epoxy-7,8,9,10-tetrahydrobenzo( a )pyrene 1 and (+)-7α,8β-dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydrobenzo( a )pyrene 1, in which the 9,10-epoxide is cis to the 7-hydroxyl group, were found to have little or no tumorigenic activity. The tumor-initiating ability of (+)-7β,8α-dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydrobenzo( a )pyrene 2 was found to be greater when given daily for 6 days at a dose of 34 nmol/day than when given once at a 200-nmol dose level. Similar fractionated doses of benzo( a )pyrene or (-)-7α,8β-dihydroxy-9β,10β-epoxy7,8,9,10-tetrahydrobenzo( a )pyrene 2 did not increase their skin tumor-initiating activity. The data suggest that (+)-7β,8α-dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydrobenzo( a )pyrene is an ultimate carcinogenic form of benzo( a )pyrene.