Tumor-initiating activity of major in vivo metabolites of indeno[1,2,3-cd]pyrene on mouse skin.

Abstract

Indeno[1,2,3-cd]pyrene is a ubiquitous environmental pollutant which is active as a tumor initiator and complete carcinogen on mouse skin and is carcinogenic in rat lung. The major metabolites of indeno[1,2,3-cd]pyrene as formed in vivo in mouse skin have been identified. 8-Hydroxyindeno[1,2,3-cd]pyrene is the most abundant metabolite identified. 9-Hydroxyindeno[1,2,3-cd]pyrene and trans-1,2-dihydro-1,2-dihydroxyindeno[1,2,3-cd]pyrene are also major in vivo metabolites in mouse skin. Several minor metabolites were also identified. Among these are trans-1,2-dihydro-1,2,8-trihydroxyindeno[1,2,3-cd]pyrene, trans-1,2-dihydro-1,2,9-trihydroxyindeno[1,2,3-cd]pyrene, indeno[1,2,3-cd]pyrene-1,2-dione, and 10-hydroxyindeno[1,2,3-cd]pyrene. The tumor-initiating activity of several of the major in vivo metabolites of indeno[1,2,3-cd]pyrene has been investigated on mouse skin. Trans-1,2-dihydro-1,2-dihydroxyindeno[1,2,3-cd]pyrene and 1,2-dihydro-1,2-epoxyindeno[1,2,3-cd]pyrene both produced an 80% incidence of tumor-bearing mice at a total initiating dose of 1.0 mg. The activity of this K-region dihydrodiol and K-region oxide was, however, less than that of the parent hydrocarbon. These data suggest that 1,2-dihydro-1,2-epoxyindeno[1,2,3-cd]pyrene, which is an ultimate mutagenic metabolite of indeno[1,2,3-cd]pyrene, is not the ultimate tumorigenic metabolite on mouse skin. 8-Hydroxyindeno[1,2,3-cd]pyrene, which is mutagenic when assayed in the presence of a microsomal activation system, exhibited only weak tumor-initiating activity. These results indicate that the principal metabolic activation pathways associated with the mutagenic activity of indeno[1,2,3-cd]pyrene are not related to its tumor-initiating activity on mouse skin.