METABOLISM AND BILIARY-EXCRETION OF BENZO[A]PYRENE 4,5-OXIDE IN THE RAT

  • 1 January 1980
    • journal article
    • research article
    • Vol. 8  (2) , 68-72
Abstract
The excretion and biliary metabolites of i.v. administered benzo[a]pyrene 4,5-oxide were studied in the rat at 2 dose levels. After administration of 4.5 or 0.47 .mu.mol, 1/2 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 not cysteinylglycine conjugate was detected. Hydration to trans-benzo[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. 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 epoxide hydrolase.