Pyrrolizidine alkaloid-induced alterations in benzo[alpha]pyrene metabolism and binding of benzo[alpha]pyrene metabolites to deoxyribonucleic acid

Pretreatment of rats by oral administration of jacobine, a pyrrolizidine alkaloid and inducer of epoxide hydrolase, produced a marked shift in hepatic microsomal metabolism in vitro of benzo[alpha]pyrene. The formation of 9-hydroxybenzo[alpha]pyrene and 7,8-dihydroxy-7,8-dihydrobenzo[alpha]pyrene was decreased whereas the formation of 4,5-dihydroxy-4,5-dihydrobenzo[alpha]pyrene was increased following jacobine treatment. This shift in the ratio of benzo[alpha]pyrene metabolites was accompanied by a significant reduction in DNA binding. Addition of purified epoxide hydrolase to control or jacobine microsomes produced a similar decrease in total DNA binding. Chromatography of benzo[alpha]pyrene metabolite-DNA nucleoside adducts showed a marked reduction in four peaks and the elimination of one peak with microsomes from jacobine-treated rats.