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Metabolism and Excretion of Benzo(a)pyrene 4,5-Oxide by the Isolated Perfused Rat Liver¹

Laboratory of Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709

Benzo(a)pyrene 4,5-oxide was metabolized in the isolated perfused rat liver by epoxide hydrase and glutathione S-transferases to the corresponding dihydrodiol and to thioether conjugates (derivatives of glutathione), respectively. Epoxide hydrase was more important relative to the glutathione S-transferases in the biotransformation of this oxide by the intact organ than was indicated by the results from earlier studies with subcellular fractions. The dihydrodiol was rapidly released into the circulation or conjugated with glucuronic acid; sulfuric acid esters were not found. All conjugated metabolites were rapidly excreted in the bile but some were also released into the circulation. The enzymatic systems responsible for the metabolism and excretion of benzo(a)pyrene 4,5-oxide remained viable in the isolated perfused liver for at least 60 min.

The toxicological significance of the release of polycyclic aromatic hydrocarbon metabolites from the liver into the vascular circulation and the possible significance of UDP:glucuronyltransferase activity in preventing chemically induced carcinogenesis are discussed.

¹ Partial support by United States Environmental Protection Agency under an interagency agreement relating to the Federal Interagency Energy/Environmental Research and Development Program.

² To whom requests for reprints should be addressed, at Laboratory of Pharmacology, National Institute of Environmental Health Sciences, P. O. Box 12233, Research Triangle Park, N. C. 27709.

Received 11/ 6/78. Accepted 3/ 5/79.