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Metallothionein (MT), which is a low-molecular weight, cysteine-rich, metal-binding protein, is induced during acute-phase reactions. However, the specific function of MT in the acute-phase response remains to be elucidated. We previously reported that MT-I, II deficient (MT-null) mice are highly sensitive to the lethal effects of lipopolysaccharide (LPS)/D-galactosamine (GalN). We designed the present study to clarify the major cause of the differences in the sensitivity to the lethal effects of LPS/GalN between wild type and MT-null mice. We found that histological grade of hepatocellular necrosis, induced by LPS/GalN, was greater in MT-null mice than in wild type mice. Therefore, the present findings suggest that MT induction has the potential as an attenuator of LPS/GalNinduced liver necrosis.

Zinc is an essential and multifunctional element for all cells. Metallothionein (MT) is a low molecular weight, cystein-rich, metal-binding protein that is involved in zinc homeostasis. During the acute-phase reaction, hepatic MT production is induced and hepatic zinc accumulation is stimulated. We previously reported that MT-I and IIdeficient (MT-null) mice are highly sensitive to the lethal effects of lipopolysaccharide (LPS) plus D-galactosamine (GalN). The sensitization may relate to attenuatoin of α 1 -acid glycoprotein (AGP) expression in MT-null mice. In the present study, we hypothesized that MT-induced hepatic zinc accumulation promotes AGP expression and prevents LPS/GalN-induced lethality. To determine whether zinc reduces LPS/GalN toxicity, zinc was administered to mice. Simultaneous administration of zinc and LPS/GalN showed no effect on the lethality of LPS/GalN in mice. Zinc administration at 3 hr prior to LPS/GalN challenge reduced LPS/GalN-induced death. However, zinc pre-administration at 24 hr before LPS/GalN challenge did not reduce LPS/GalN-induced death. The expression of AGP mRNA was elevated at 3 hr after zinc administration, 24-hr pretreatment was ineffective. The protective effect of zinc was observed in both wild-type and MT-null mice. These results show that the protective effects of zinc were not caused by MT induction, but by AGP expression. We suggest that MT-induced hepatic zinc accumulation may promote AGP expression and thus prevent LPS/GalN-induced lethality.