Interspecies comparisons of benzo(a)pyrene metabolism and DNA-adduct formation in cultured human and animal bladder and tracheobronchial tissues.

Cultured bladder and tracheobronchial explants from human, monkey, dog, hamster, and rat were used to study the metabolism, covalent binding to DNA, and DNA-adduct formation of [3H]benzo( a )pyrene (BP). Both organs from all species formed large amounts (40 to 70% of total 3H in the medium after 24 hr of incubation) of polar material and small amounts (<1% for animal tissues and 1 to 5% for human tissues) of organic solvent-extractable (unconjugated) metabolites, with the balance (14 to 38%) being unmetabolized BP. Patterns of unconjugated BP metabolites revealed qualitatively similar metabolism in the various species, with (±)-7β,8α,9α,10β-tetrahydroxy-7,8,9,10-tetrahydrobenzo( a )pyrene, trans -9,10-dihydro-9,10-dihydroxybenzo( a )pyrene, trans -4,5-dihydro-4,5-dihydroxybenzo( a )pyrene, trans -7,8-dihydro-7,8-dihydroxybenzo( a )pyrene, phenols, and quinones constituting identifiable metabolites. Relative proportions of these metabolites differed between organs and between species. Total metabolism was highest in human tissues and lowest in rat tissues. Purification of [3H]BP:DNA from the explants revealed that covalent binding (µmol of BP per mol of deoxyribonucleotide) was significantly higher in human bladder [6.4 ± 5.3 (S.D.)] and bronchus (3.1 ± 2.0) than in the corresponding animal bladder (0.8 to 2.4) and tracheobronchial (0.8 to 3.4) tissues. Hydrolysis of [3H]BP:DNA to the nucleoside level showed that, in most cases, 7 R-N 2-(10β-[7β,8α,9α-trihydroxy-7,8,9,10-tetrahydrobenzo( a )pyrene]yl)deoxyguanosine was the major DNA adduct formed, with smaller amounts of the corresponding 7 S enantiomer and of N 2-(10α[7β,8α,9β-trihydroxy-7,8,9,10-tetrahydrobenzo( a )pyrene]yl)deoxyguanosine. Two unidentified adducts (possibly deoxycytidine adducts) were formed by both tissues of all species and, in dog and rat bladder explants, one of these constituted the largest proportion of [3H]BP:DNA adducts. A product, tentatively designated to be an adduct between 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo( a )pyrene and deoxyadenosine, was formed by rat tissues only and not by tissues from the other species. It is concluded that bladder and tracheobronchial tissues of the human, monkey, dog, hamster, and rat metabolize BP in vitro in a qualitatively similar manner and that only a small percentage of the metabolites can be identified. Among the species studied, human tissues are most active in metabolizing BP and exhibit the highest covalent binding of BP to DNA. At least four BP:DNA adducts can be detected in both tissues of all species, the most abundant one, in most cases, being the adduct derived from the most carcinogenic of the known BP metabolites. Further, the distribution of BP:DNA adducts is specific and reproducible for each species.