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Metallothionein Expression Protects against Carbon Tetrachloride-Induced Hepatotoxicity, but Overexpression and Dietary Zinc Supplementation Provide No Further Protection in Metallothionein Transgenic and Knockout Mice¹

Steven R. Davis^*, Don A. Samuelson and Robert J. Cousins^*2

^* Food Science and Human Nutrition Department, Center for Nutritional Sciences, and Small Animal Clinical Sciences Department, University of Florida, Gainesville, Florida 32611-0370

²To whom correspondence should be addressed at Food Science and Human Nutrition Department, University of Florida, 201 FSHN, P.O. Box 110370, Gainesville, FL 32611-0370. E-mail: rjc{at}gnv.ifas.ufl.edu

Metallothionein and zinc have been implicated in cellular defense against a number of cytotoxic agents. With respect to the free radical–generating hepatotoxin carbon tetrachloride, conclusions about a defensive role were reached from in vitro studies, in vivo studies using inducers of metallothionein and studies using injections of pharmacological amounts of zinc. Metallothionein knockout (null) and metallothionein transgenic mice are more direct models to examine the effects of metallothionein expression on induced cytotoxicity. Similarly, zinc presented via the diet is a more physiological model than that presented via injection. We examined whether metallothionein-overexpressing mice or metallothionein knockout mice had altered sensitivity to carbon tetrachloride and whether supplemental dietary zinc reduced sensitivity to carbon tetrachloride in these genotypes. Metallothionein knockout mice produced no metallothionein and were unable to sequester additional hepatic zinc in response to elevated dietary zinc. Hepatotoxicity, as measured by serum alanine aminotransferase activity, histological analyses and hepatic thiol levels, was greater in the knockout mice than in controls 12 h after carbon tetrachloride treatment but not at later time points (up to 48 h). In contrast, metallothionein-overexpressing mice produced more metallothionein and sequestered more liver zinc than control mice, but hepatotoxicity was similar between genotypes. Supplemental dietary zinc had no effect on hepatotoxicity with either genotype. These data suggest metallothionein null mice were more susceptible to carbon tetrachloride–induced hepatotoxicity than were control mice. However, neither metallothionein overexpression nor supplemental dietary zinc provided further protection.

KEY WORDS: • zinc • metallothionein • oxidative stress • knockout • transgenic • mice

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