Metabolism and DNA binding of benzo(a)pyrene in vivo in the rat.

The in vivo metabolism and DMA binding of benzo(a)pyrene (BP) was examined in male Sprague-Dawley rat. BP was ad ministered i.v. at dose levels of 1.0 and 10.0 /¿mol/kg. DNA samples from [3H]BP-treated rats were enzymatically digested to deoxyribonucleosides and analyzed by high-pressure liquid chromatography. Several chromatographically distinct nucleoside-bound adducts were observed in lung whereas in the liver only one adduci was apparent. The major adduct formed in the lung was chromatographically identical to the adduct formed in the liver and represented 42 and 7% of total DNA binding in lung and liver, respectively. The major adduct (II) appeared to result from further metabolism of BP phenols. The BP diolepoxide adducts were not detected in rat liver, and only a relatively small amount was observed in rat lung, 1.4% of total DNA binding. The lack of formation of substantial amounts of BP diol-epoxide adducts in rat lung is consistent with the apparent lack of induction of pulmonary tumors in rat by BP. The BP-DNA adduct profiles were similar at both dose levels. Comparisons between the observed in vivo BP-DNA adduct profiles and profiles in various in vitro model systems are made. Bile samples were collected from bile-cannulated animals following i.v. dose of BP. With a 1.0-fimol/kg dose of BP, 68% of the dose was excreted into bile in six hr, and of this amount 34 and 9% represented glucuronide and sulfate conjugates, respectively. The remaining biliary metabolites were probably glutathione conjugates. Glucuronide and sulfate conjugates of phenols, diols, quiñones, and uncharacterized more polar me tabolites (pre-9,10) were detected in bile. The benzo(a)pyrene3,6-dione, 6.5% of dose, and pre-9,10, 9% of dose, were the major glucuronide metabolites. The pre-9,10 metabolites are probably polyhydroxylated BP derivatives recycled through the monooxygenase enzymes. Adduct II is probably formed from the interaction of DNA with reactive intermediates generated in the formation of pre-9,10 metabolites.