Oleanolic acid protects against cadmium hepatotoxicity by inducing metallothionein.
Oleanolic acid (OA) is a triterpenoid compound that has been shown to protect against some hepatotoxicants and is used in China to treat hepatitis. This study was conducted to examine the protective effects of OA against cadmium (Cd)-induced liver injury in mice and the mechanism of protection. OA (100 mg/kg x 3 days) pretreatment dramatically decreased Cd (3.7 mg/kg i.v.)-induced liver injury as indicated by decreased serum activities of alanine aminotransferase and sorbitol dehydrogenase, as well as by histopathological observation. To examine the mechanism of protection, the distribution of Cd to major organs and the hepatic subcellular distribution of Cd were determined 2 hr after 109Cd injection (3.5 mg/kg of Cd and 10 microCi/mg of Cd i.v.). OA did not reduce the amount of Cd in liver, but significantly altered the hepatic subcellular distribution of Cd, with more Cd in hepatic cytosol bound to metallothionein (MT), and with less Cd in other organelles and proteins. OA produced an approximately 30-fold increase in hepatic MT, but had no appreciable effects on MT levels of five other organs. Furthermore, OA increased both hepatic MT-I and MT-II levels, as determined by high-performance liquid chromatography/atomic absorption spectrophotometry. Northern blot analysis revealed that OA increases MT mRNA expression. In summary, OA pretreatment protects against Cd-induced hepatotoxicity by inducing MT. MT bound Cd in the cytosol, and thus decreased the amount of Cd in other critical organelles and proteins. OA is a hepatic MT inducer for both MT-I and MT-II isoforms, and this effect is due, at least in part, to an increased MT mRNA accumulation.
Liu
Y
Y
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City.
Kreppel
H
H
Liu
J
J
Choudhuri
S
S
Klaassen
C D
CD
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D015152:Blotting, Northern; D002104:Cadmium / Q000493:pharmacokinetics / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007536:Isomerism; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood; D008099:Liver / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D008668:Metallothionein / Q000096:biosynthesis*; D051379:Mice; D008815:Mice, Inbred Strains; D009828:Oleanolic Acid / Q000627:therapeutic use*; D009929:Organ Size / Q000187:drug effects; D015347:RNA Probes; D012333:RNA, Messenger / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D014018:Tissue Distribution
D015347:RNA Probes; D012333:RNA, Messenger; D002104:Cadmium; D009828:Oleanolic Acid; D008668:Metallothionein; D007064:L-Iditol 2-Dehydrogenase; D000410:Alanine Transaminase