Role of metallothionein in cadmium-induced hepatotoxicity and nephrotoxicity

MT, a cysteine-rich, metal-binding protein, exists in most tissues and is easily induced by many stimuli. There are four major MT isoforms in mammalian tissues, with MT-I and -II present in all tissues, MT-III only in brain, and MT-IV located in epithelium. Many factors regulate MT synthesis, such as age, species, hormones, inflammation, and various chemical treatments. Not only is MT synthesis important, but degradation of MT is also an important mechanism of MT regulation. The importance of MT in Cd toxicology has been extensively investigated. MT does not have a major effect on absorption and tissue distribution of Cd, but it does play a major role in binding Cd in the cell, thus decreasing its elimination from the body, especially into the bile. MT is at least partially responsible for the retention of Cd in tissues and the long biological half-life of the metal. MT plays an important role in Cd tolerance and Cd-induced hepatotoxicity. MT binds Cd in the hepatic cytosol and renders it "inert." Therefore, MT is beneficial to the liver. However, the Cd-MT complex is nephrotoxic and is proposed to be responsible for chronic Cd poisoning. MT appears to play less of a protective role in Cd-MT-induced acute nephrotoxicity, and Zn-induced protection against CdMT acute renal injury is not mediated by MT. The role of MT in chronic Cd nephrotoxicity needs to be further clarified.