Kinetics of uptake and biliary excretion of benzo(alpha)pyrene and mutagenic metabolites in isolated perfused rat liver.
An isolated liver perfusion system was used as a simplifying tool to study the metabolism and excretion of benzo(alpha)pyrene (BP) as a prototype carcinogen/mutagen. Phenobarbital (PB) was used to induce liver microsomal enzymes in Sprague-Dawley male rats prior to isolated liver perfusion. Control livers were run simultaneously using generally tritiated (G-3H)BP/BP as substrate in the perfusion medium. Both biliary excretion and liver weight were increased in the induced compared to control liver, but biliary flow when corrected for liver weight is statistically the same for both control and PB-induced livers. The excretion rat of radioactivity in the bile is always higher for PB-induced than for control liver (maximum radioactive excretion at 1 hr). There is a more rapid radioactivity removal in the liver perfusion medium for PB-induced than for control livers. Data are explained by increased metabolism of BP in induced liver leading to the presence of more polar metabolites undergoing preferential biliary excretion than in the control liver. Results support in vivo experimental data. Extracts from liver and bile were tested for microbial mutagenicity by the Ames test (TA 100) after TLC separation. The control liver shows virtually no mutagenicity in bile, only in TLC fractions from the liver. The PB-induced liver shows significant mutagenicity in several TLC fractions in both bile and liver. The net effect of induction is to produce more mutagenic metabolites of BP, excreted in the bile, and presenting a significant exposure of carcinogens/mutagens, and consequent hazard to man.
D000818:Animals; D001564:Benzo(a)pyrene; D001580:Benzopyrenes / Q000378:metabolism*; D001646:Bile / Q000378:metabolism*; D001711:Biotransformation; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D009152:Mutagenicity Tests; D009153:Mutagens / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D001580:Benzopyrenes; D009153:Mutagens; D001564:Benzo(a)pyrene; D010634:Phenobarbital