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J.Health Sci., 49(1), 40-44, 2003
Protective Effect of Zinc against
Lipopolysaccharide/D-Galactosamine-Induced Lethality
Tomoki Kimura,a,
b Norio Itoh,*, a Miyako
Takehara,a Ikuyo
Oguro,a Jun-ichi
Ishizaki,a Tsuyoshi
Nakanishi,a Masakazu
Isobe,b and Keiichi
Tanakaa
aDepartment of Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka
565-0871, Japan and bDepartment of Toxicology, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho,
Hirakata, Osaka 573-0101, Japan
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 II-deficient (MT-null) mice are highly sensitive to the lethal effects of lipopolysaccharide (LPS) plus D-galactosamine (GalN). The sensitization may relate to attenuatoin of alpha1-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.
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