Identification of mutagenic metabolites of indeno[1,2,3-cd]pyrene formed in vitro with rat liver enzymes

Indeno[1,2,3-cd]pyrene (IP) is a major environmental pollutant which is carcinogenic on mouse skin and in rat lung. Unlike benzo(a)pyrene, IP is a nonalternant polycyclic aromatic hydrocarbon which is devoid of a bay region. IP was mutagenic in Salmonella typhimurium TA100 in the presence of a 9000 X g supernatant from the livers of Aroclor-pretreated rats. Using a similar activation system, the major metabolites of IP were isolated and identified by comparison with synthetic reference standards. trans-1,2-Dihydro-1,2-dihydroxy-IP, 8-, 9-, and 10-hydroxy-IP, 8- and 9-hydroxy-trans-1,2-dihydro-1,2-dihydroxy-IP, and IP-1,2-quinone are among the metabolites formed in vitro. The 1,2-epoxide of indeno[1,2,3-cd]pyrene is a potent direct-acting mutagen. 8- and 9-hydroxy-IP were mutagenic with metabolic activation. 1-,2-, and 6-hydroxy-IP and the trans-1,2-dihydrodiol had no significant mutagenic activity in S. typhimurium TA100 with metabolic activation. These data suggest that the K-region oxides of IP and of 8- and 9-hydroxy-IP are ultimately responsible for its mutagenic activity.