Protective effects of oleanolic acid on acetaminophen-induced hepatotoxicity in mice.
Oleanolic acid (OA) is a triterpenoid compound that has been shown to protect against a number of hepatotoxicants, and is used in China to treat hepatitis. In the present study, we examined the effect of OA on acetaminophen (AA)-induced acute liver injury in mice and the mechanism(s) of protection. OA pretreatment (25-100 mg/kg s.c. for 3 days) remarkably decreased AA (500 mg/kg i.p.)-induced liver damage in mice, as indicated by decreased serum activities of alanine aminotransferase and sorbitol dehydrogenase, as well as by histopathological observation. Additionally, OA pretreatment mitigated AA (300-450 mg/kg i.v.)-induced depletion in liver glutathione (GSH) content. The protective effect was not evident until 24 hr after a single s.c. injection of OA (300 mg/kg) and lasted for 72 hr. To examine the mechanism of this protection, the biliary and urinary excretion of AA and AA metabolites were measured for 2 hr after AA administration (150 mg/kg i.v.) in bile duct-cannulated mice. OA pretreatment resulted in an increased urinary excretion of AA-glucuronide and a decreased biliary excretion of AA-GSH. Microsomes from OA-pretreated mice, incubated in vitro with AA, produced less benzoquinoneimine intermediate than controls, as determined by the formation of AA-GSH. Hepatic subcellular distribution of [3H] AA to the nuclear fraction was also decreased by OA. OA pretreatment of mice had no influence on liver UDP-glucuronic acid concentration, but increased hepatic glucuronosyltransferase activity toward AA. In summary, OA pretreatment dramatically protects against AA-induced hepatotoxicity in mice.(ABSTRACT TRUNCATED AT 250 WORDS)
Liu
J
J
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City.
Liu
Y
Y
Madhu
C
C
Klaassen
C D
CD
D000082:Acetaminophen / Q000493:pharmacokinetics / Q000633:toxicity* / Q000652:urine; D000818:Animals; D001659:Biliary Tract / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury; D004305:Dose-Response Relationship, Drug; D014453:Glucuronosyltransferase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009828:Oleanolic Acid / Q000627:therapeutic use*; D013347:Subcellular Fractions / Q000378:metabolism; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism
D014535:Uridine Diphosphate Glucuronic Acid; D000082:Acetaminophen; D009828:Oleanolic Acid; D014453:Glucuronosyltransferase; D005978:Glutathione