Metabolism and biliary excretion of benzo[a]pyrene 4,5-oxide in the rat

The excretion and biliary metabolites of intravenously administered benzo[a]pyrene 4,5-oxide were studied in the rat at two dose levels. After administration of 4.5 or 0.47 mumol, half of the dose was excreted in the bile in 60 min. Biliary metabolites were separated by reverse-phase high-pressure liquid chromatography and identified by cochromatography with biosynthetic standards, beta-glucuronidase hydrolysis, ultraviolet spectrophotometry and, in the case of the thioether conjugates, identification of the constituent amino acids. The major biliary metabolite was a mixture of isomeric glutathione conjugates. Some cysteine conjugate was also present, but no cysteinylglycine conjugate was detected. Hydration to transbenzo[a]pyrene-4,5-dihydrodiol followed by glucuronidation was also a quantitatively important metabolic pathway. Although benzo[a]pyrene-4,5-dihydrodiol glucuronide was more readily excreted by the liver than was benzo[a]pyrene 4,5-oxide:glutathione conjugate, the rate of glucuronidation of the dihydrodiol was low, resulting in its accumulation in the liver and possible release into the circulation. Therefore, the glutathione S-transferases may provide a more efficient mechanism for the removal of benzo[a]pyrene 4,5-oxide from the body than is provided by expoxide hydrolase.