Chemical forms of metallothionein and cellular oxidative stress in human hepatocellular carcinoma: A comparative study with the hepatitis of LEC rat

Metallothionein (MT) has been described as a cell-protective protein that binds several heavy metals. In mammals, MT plays an important physiological role that includes detoxifying heavy metals, accumulating essential trace elements in cells to maintain homeostasis, and scavenging reactive oxygen species or free radicals. In contrast, the generation of hydroxyl radical (·OH) has been reported in the reaction of hydrogen peroxide and copper (Cu)-MT separated from the livers of Long–Evans Cinnamon (LEC) rats, an animal model of human hepatic injury with unusual accumulation of Cu-MT in the liver. On the other hand, Cu has been reported to accumulate in human hepatocellular carcinoma (HCC). Thus, we investigated whether the induction of MT, accumulation of Cu, and enhancement of oxidative stress are relevant to the development of human HCC, similarly to the observations in the liver of LEC rats. Although the kinetic behaviors of metal and MT levels were different in the livers of humans and LEC rats, Cu-MT induction in the tumor portion of human HCC tissues was suggested to occur similarly to that in the liver of LEC rats. In addition, it was found that oxidative stress in terms of the level of thiobarbituric acid-reactive substances was enhanced in the tumor portion of human HCC, corresponding well with increasing in the age of LEC rats, which developed jaundice and hepatitis. On the basis of these results, we conclude that the induction of Cu-MT in human HCC might be related to the hepatic oxidative stress, which in turn develops hepatic injury involving carcinoma. J. Trace Elem. Exp. Med. 15:31–45, 2002. ©2002 Wiley-Liss, Inc.