Hepatic and renal conjugation (Phase II) enzyme activities in young adult, middle-aged, and senescent male Sprague-Dawley rats.
Acetaminophen (APAP)-induced nephrotoxicity is age dependent in male Sprague-Dawley rats: nephrotoxicity occurs at lower dosages of APAP in 12- to 14-month olds compared with 2- to 3-month olds. The mechanisms responsible for enhanced nephrotoxicity in 12-month-old Sprague-Dawley rats are not entirely clear, but may be related to age-dependent differences in APAP metabolism in liver and/or kidney. Major pathways of hepatic APAP metabolism include sulfation and glucuronidation; glutathione conjugation represents a pathway for detoxification of reactive oxidative APAP metabolites. The present studies were designed to quantify in vitro activity of three Phase II enzyme activities: glutathione S-transferase using 1-chloro-2,4-dinitrobenzene as substrate, UDP-glucuronyl transferase using APAP as substrate, and sulfotransferase using APAP as substrate, in subcellular fractions of liver and kidney of 3-, 12-, 18-, and 30-month-old naive male Sprague-Dawley rats. In liver, glutathione S-transferase, UDP glucuronyl transferase, and sulfotransferase activities were not significantly different in rats from 3 through 30 months of age. Renal UDP glucuronyl transferase and sulfotransferase activities were similar in rats from 3 through 30 months of age. In contrast, renal glutathione S-transferase activity was characterized by a lower Km in 12- and 30-month olds when compared with 3-month olds. These data suggest that the reduced total systemic clearance of APAP in 12-month-old male Sprague-Dawley rats previously observed cannot be attributed to age-dependent differences in hepatic APAP metabolism. In addition, it is unlikely that differences in renal APAP metabolism contribute to age-dependent APAP nephrotoxicity.
Tarloff
J B
JB
Department of Investigative Toxicology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939.
Goldstein
R S
RS
Sozio
R S
RS
Hook
J B
JB
D000082:Acetaminophen / Q000378:metabolism / Q000633:toxicity; D000375:Aging / Q000378:metabolism*; D000818:Animals; D014453:Glucuronosyltransferase / Q000032:analysis; D005982:Glutathione Transferase / Q000032:analysis; D007668:Kidney / Q000201:enzymology*; D008099:Liver / Q000201:enzymology*; D008297:Male; D009929:Organ Size; D051381:Rats; D011919:Rats, Inbred Strains; D015238:Sulfotransferases / Q000032:analysis
D000082:Acetaminophen; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase; D015238:Sulfotransferases