Distribution of Zinc‐Binding Metallothionein in Cirrhotic Liver of Rats Administered Zinc

Abstract

This study was undertaken in order to investigate the effect of zinc (Zn) administration on induction of Znbinding metallothionein in rat liver with thioacetamide-induced cirrhosis, and the localization of metallothionein in the liver. Normal and cirrhotic rats received intraperitoneal injections with or without Zn. Subsequently, metal analyses, purification of metallothionein by gel filtration and immunohistochemical assessments of metallothionein were carried out. Although in Zn-injected cirrhotic rats, the Zn contents in the liver and plasma increased significantly depending upon the dose of Zn, the Zn contents in the liver and plasma of the cirrhotic rats were lower than those of normal rats after the same dose of Zn. The results of gel filtration also showed that the levels of Zn-metallothionein in the cirrhotic liver were reduced in comparison with those of the normal liver. By the immunohistochemical method, the presence of metallothionein in the parenchymal areas but not in the fibrotic areas of the cirrhotic liver was confirmed. These results suggested that the induced metallothionein was only located in the parenchymal areas. The metallothionein induced in the parenchymal areas was considered to play a role in protecting the parenchymal cells against the progression of fibrosis, because metallothionein has been thought to be involved in the cellular defense against oxidative stress.Zinc (Zn) is an essential trace element for several metabolic processes. For example, Zn is believed to be associated with a protective action in liver cell activity and possible prevention of cellular damage caused by oxidative stresses (Bray & Better 1990). In Zn-loaded human and Zn-exposed experimental animals, a major Zn-binding protein in tissues such as liver and kidney has been identified as metallothionein. This protein is also known to be induced in cultured cells such as fibroblasts (Cherian 1980;Liu et al. 1990).Metallothionein is a low molecular weight, cysteine-rich protein and binds with high affinity metal ions, such as Zn(II), copper (Cu) (I) and cadmium (Cd) (II). Although the precise functions of metallothionein have not yet been clarified, this protein is believed to play important roles in the homeostasis of trace elements such as Zn and Cu and in detoxification of heavy metals such as Cd and mercury (Kägi & Kojima 1987).So far, several experiments have assessed the beneficial effect of Zn supplementation on liver diseases such as advanced cirrhosis and alcoholic disease. Zn treatments in experimental cirrhotic rats were shown to increase the hepatic activity of ornithine transcarbamoylase, which is an enzyme in hepatic urea synthesis (Riggio et al. 1992). Moreover, Zn Author for correspondence: M. Kurasaki, Department of Environmental Medicine and Informatics, Graduate School of Environmental Earth Science, Hokkaido University, Sapporo 060-0810 Japan (e-mail kura/ees.hokudai.ac.jp).administration efficiently inhibits collagen accumulation in cirrhotic rats (Anttinen et al. 1984;Giménez et al. 1...

Cell proliferation and hepatocarcinogenesis in rat initiated by diethylnitrosamine and promoted by phenobarbital: Potential roles of early DNA damage and liver metallothionein expression

“…A significant reduction in serum and intracellular Zn levels in HCC patients, and almost all tumor tissues having reduced Zn levels were observed in several studies, reported by Poirier (1996), Ebara et al (2000), Hatano et al (2000), and Maeda et al (2005). It has also been found that, Zn contents in the tumor and cirrhotic liver tissues were significantly lower than that of the adjacent nontumor "normal" tissues which had again lowered Zn levels than normal tissues (Liaw et al, 1997;Sato et al, 2000;Tashiro et al, 2003). Reports further demonstrated that hepatic Zn levels gradually decreased as the hepatocellular lesions progressed from premalignancy to frank malignancy via the late premalignant phase (Nakayama et al, 2002a,b;Kubo et al, 2005) and studies by Eagon et al (1999) showed that Zn levels temporally decreased in hyperplasic rat liver than that of the normal counterpart.…”

Modulation of metallothionein isoforms is associated with collagen deposition in proliferating keloid fibroblasts in vitro

“…There is also evidence in the literature which supports the notion that modulation of MT is associated with fibrosis. Relating the occurrence of fibrosis to MT, Sato et al (45) have also suggested that MT might contribute to protection of parenchymal cells in the liver against progression of fibrosis. The same investigators observed that MT was absent in fibrotic areas but present in non-fibrotic parenchymal cells.…”

Zinc and the Liver: An Active Interaction

“…Contrary to MT overexpression in cases of acute liver injury, chronic liver disease was associated with reduced hepatic MT levels [174], although it has been reported that different types of chronic liver disease express different levels of MT. Thus, MT expression was reduced in HCC tissue [175], increased in the liver of PBC patients [96], highly elevated in the liver of patients with Wilson's disease [96], or even unaffected in cirrhotic tissue compared with normal hepatic parenchyma [175].…”

“…Zn administration at the early stage of fibrosis induction increased the hepatic MT levels and, thus, oxidative stress [141] and apoptosis [66] were controlled. Nevertheless, when cirrhosis was already induced in rats, Zn administration increased MT expression only in normal hepatic parenchyma but not in the fibrotic tissue [174].…”