Drug metabolizing enzyme changes after chronic buthionine sulfoximine exposure modify acetaminophen disposition in rats

• Published in: Drug metabolism and disposition Vol. 19; no. 2; p. 498
• Main Authors: Manning, B W, Franklin, M R, Galinsky, R E
• Format: Journal Article
• Language: English
• Published: United States 01-03-1991
• Subjects: Acetaminophen - metabolism; Acetaminophen - pharmacokinetics; Animals; Antimetabolites - pharmacology; Biotransformation; Buthionine Sulfoximine; Cytochrome P-450 Enzyme System - metabolism; Glucuronates - metabolism; Glutathione - metabolism; In Vitro Techniques; Male; Methionine Sulfoximine - analogs & derivatives; Methionine Sulfoximine - pharmacology; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; Mixed Function Oxygenases - metabolism; Rats; Rats, Inbred Strains; Sulfates - metabolism
• ISSN: 0090-9556

This study examined the effects of prolonged exposure to buthionine sulfoximine (BSO) on 1) the overall elimination pharmacokinetics of acetaminophen; 2) the sulfate and glucuronide conjugation processes primarily responsible for acetaminophen elimination; and 3) in vitro microsomal and cytoplasmic enzyme activities in rats. Rats imbibed drinking water containing 30 mM BSO for 6 days and then received an iv injection of acetaminophen, 150 mg/kg in a propylene glycol vehicle. Exposure to BSO, a specific inhibitor of gamma-glutamylcysteine synthetase, produced marked depletion of glutathione (GSH) and resulted in induction of hepatic UDP-glucuronosyltransferase and GSH-S-transferase enzyme activities, but not cytochrome P-450. BSO pretreatment had no effect on the total or renal clearance of acetaminophen in rats. However, BSO exposure increased the partial clearance of acetaminophen to acetaminophen glucuronide by 47% (1.29 +/- 0.08 vs. 1.90 +/- 0.23 ml/min/kg; p less than 0.01) and significantly (p less than 0.02) increased the percentage of the dose recovered as the glucuronide conjugate from 17.6 +/- 2.5 to 26.5 +/- 0.6 The partial clearance of acetaminophen to acetaminophen sulfate was decreased, although not significantly, from 4.46 +/- 0.62 to 3.39 +/- 0.82 ml/min/kg. BSO treatment increased microsomal UDP-glucuronosyltransferase activity toward three xenobiotic aglycones, p-nitrophenol, 1-naphthol, and morphine by 308, 61, and 66%, respectively (p less than 0.05), but not toward testosterone or estrone. Cytosolic GSH-S-transferase activity toward 1-chloro-2,4-dinitrobenzene was increased 52% by BSO, whereas p-nitrophenol sulfotransferase activity was not altered. Cytochrome P-450 concentration and monooxygenase activity were unchanged by BSO exposure.