Changes in conjugative enzyme activity and acetaminophen metabolism in young and senescent male F-344 rats following prolonged exposure to buthionine sulfoximine.
This study examined how advanced age affects glucuronide and sulfate conjugation of acetaminophen after prolonged exposure to L-buthionine-S,R-sulfoximine (BSO) in male Fischer 344 rats. Young (4-5 month) and senescent (21-22 month) rats received 11 doses of BSO (2 mmol/kg) at 12-h intervals via a gastric cannula. Hepatic metabolism was assessed in vivo by measuring the products of reactions mainly responsible for acetaminophen elimination, namely the formation of the glucuronide and sulfate conjugates. Selected drug-metabolizing enzyme activities were also determined in vitro. BSO treatment increased the partial clearance to acetaminophen glucuronide by 90% and 41% in young and old rats, respectively, and similarly, induced p-nitrophenol and 1-naphthol UDP-glucuronosyl transferase activities to a greater extent in young versus senescent animals. Thus, the induction of these UDP-glucuronosyl transferase activities by BSO is preserved in senescent animals. Although the partial clearance to acetaminophen sulfate was decreased in senescent control rats compared to young controls, BSO treatment decreased the in vivo rate of sulfation in both age groups. Similar to previous findings with the Sprague-Dawley strain, BSO treatment did not induce hepatic cytochrome P-450 content or activity or cytosolic p-nitrophenol sulfotransferase activity in young and senescent Fischer 344 rats.
Galinsky
R E
RE
Department of Pharmaceutics, College of Pharmacy, University of Utah, Salt Lake City 84112.
Manning
B W
BW
Kimura
R E
RE
Franklin
M R
MR
D000082:Acetaminophen / Q000378:metabolism*; D000375:Aging / Q000502:physiology*; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology*; D019328:Buthionine Sulfoximine; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010090:Oxidoreductases, O-Demethylating / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D015238:Sulfotransferases / Q000378:metabolism
D000963:Antimetabolites; D008717:Methionine Sulfoximine; D000082:Acetaminophen; D019328:Buthionine Sulfoximine; D003577:Cytochrome P-450 Enzyme System; C026048:4-nitroanisole O-demethylase; D010090:Oxidoreductases, O-Demethylating; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase; D015238:Sulfotransferases; D005978:Glutathione