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 hep atitis. 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 decr eased Cd (3.7 mg/kg i.v.)-induced liver injury as indicated by decreas ed serum activities of alanine aminotransferase and sorbitol dehydroge nase, as well as by histopathological observation. To examine the mech anism of protection, the distribution of Cd to major organs and the he patic subcellular distribution of Cd were determined 2 hr after Cd-109 injection (3.5 mg/kg of Cd and 10 muCi/mg of Cd i.v.). OA did not red uce the amount of Cd in liver, but significantly altered the hepatic s ubcellular distribution of Cd, with more Cd in hepatic cytosol bound t o metallothionein (MT), and with less Cd in other organelles and prote ins. OA produced an approximately 30-fold increase in hepatic MT, but had no appreciable effects on MT levels of five other organs. Furtherm ore, OA increased both hepatic MT-I and MT-II levels, as determined by high-performance liquid chromatography/atomic absorption spectrophoto metry. Northern blot analysis revealed that OA increases MT mRNA expre ssion. In summary, OA pretreatment protects against Cd-induced hepatot oxicity 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 h epatic 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.