Protective effects of oleanolic acid on acetaminophen-induced hepatotoxicity in mice
Liu, J.; Liu, Y.; Madhu, C.; Klaassen, C.D.
Journal of Pharmacology and Experimental Therapeutics 266(3): 1607-1613
1993
ISSN/ISBN: 0022-3565 PMID: 8371159 Document Number: 420287
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. The mechanism of this protection appears to be due, at least in part, to the decreased formation of toxic metabolites of AA, as well as increased detoxication by enhanced glucuronidation of AA.