Role of the Cyclopenta Epoxide in Metabolic Activation of the Genotoxic Cyclopentafused Derivative of Benzo[e]pyrene, Naphtho[1,2,3-mno]Acephenanthrylene

Abstract

Naphtho[1,2,3-mno]acephenanthrylene, a cyclopenta-fused derivative of benzo[e]pyrene more mutagenic than benzo[e]pyrene in the Salmonella typhimurium plate incorporation assay, was shown to be metabolized by Aroclor 1254-treated rat liver S9 principally to the cyclopenta dihydrodiol, trans 3,4-dihydroxy-3,4-dihydronaphtho[1,2,3-mno]acephenanthrene. Since the metabolic profile indicated that the cyclopenta epoxide was quantitatively the major intermediate formed, this epoxide was synthesized, by oxidation of the parent hydrocarbon with dimethyldioxirane. Direct-acting mutagenic potency was about 200 revertants per nanomol in strain TA98, approximately five times that previously reported for the parent hydrocarbon. The activity of the epoxide was decreased, but not entirely abolished, in the presence of S9. Epoxidation at the cyclopenta-fused ring can therefore account for much of the genotoxicity of naphtho[1,2,3-mno]acephenanthrylene in the Salmonella typhimurium plate incorporation assay system.

Key Words:

• Cyclopentafused benzo[e]pyrene
• naphtho[1,2,3-mno]acephenanthrene
• polycyclic aromatic hydrocarbons
• metabolism
• mutagenicity
• metabolic activation.