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Inhibition of Glucuronidation of Benzo(a)pyrene Phenols by Long-Chain Fatty Acids¹

Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599 [Z. Z., R. G. T.], and Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey 08854 [F. C. K.]

Long-chain fatty acids inhibit glucuronidation of benzo(a)pyrene phenols in perfused liver; therefore, this study was designed to investigate interactions of fatty acids with ß-glucuronidase, glucuronosyl transferase, and energy supply. In ß-glucuronidase-deficient C3H/He mice, infusion of oleate (250 µM) increased the release of free benzo(a)pyrene phenols from 14 to 33 nmol/g/h and decreased release of glucuronides into the perfusate from 25 to 17 nmol/g/h. Rates of accumulation of glucuronides in the liver were also diminished from 11 to 4 nmol/g/h after infusion of oleate (250 µM). Fatty acids did not affect the release of benzo(a)pyrene metabolites into bile, and the ratio of free phenol to glucuronide production was increased from 0.57 to 1.30. A similar trend was observed in livers from DBA/2 mice that have ß-glucuronidase. Rates of hydrolysis of benzo(a)pyrene-O-glucuronide were not altered in isolated microsomes by addition of oleoyl coenzyme A (CoA) or octanoyl CoA (10–100 µM). Thus, we conclude that fatty acids do not alter glucuronidation by acting on ß-glucuronidase.

The concentration of cofactors (UDP-glucuronic acid, UDP-glucose, and adenine nucleotides) involved in hepatic conjugation was not altered by infusion of concentrations of oleate (300 µM) that inhibited glucuronidation in perfused livers. When oleate concentrations were increased to 600 µM, UDP-glucuronic acid and UDP-glucose decreased 44 and 49%, respectively, and the ATP:ADP ratio declined concomitantly.

Oleoyl CoA inhibited UDP-glucuronosyl transferase noncompetitively (half-maximal inhibition, 10 µM) in microsomes with 3-hydroxylbenzo(a)pyrene or p-nitrophenol as substrate. In contrast, octanoyl CoA was a very poor inhibitor of transferase activity. Inhibition of the transferase by oleoyl CoA was increased markedly by treatment with detergents (Triton X-100), i.e., half-inhibition of glucuronosyl transferase was obtained with about 2 µM oleoyl CoA. Inhibition of UDP-glucuronosyl transferase by oleoyl CoA was also increased in a dose-dependent manner by albumin, possibly due to increasing access of the CoA derivative to the enzyme. Collectively, these data indicate that fatty acids diminish glucuronidation via the formation of acyl CoA compounds that inhibit UDP-glucuronosyl transferase noncompetitively.

¹ Supported in part by Grant CA-20807 from The National Cancer Institute.

² To whom requests for reprints should be addressed, at University of North Carolina at Chapel Hill, CB# 7365, Faculty Laboratory Office Building, Chapel Hill, NC 27599-7365.

Received 11/13/90. Accepted 6/14/91.