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Metallothionein I and II Protect against Zinc Deficiency and Zinc Toxicity in Mice^1,2,

Department of Biochemistry and Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195-7370

Metallothionein (MT)-bound zinc accumulates when animals are exposed to excess zinc and is depleted under conditions of zinc deficiency, suggesting that MT serves as a means of sequestering excess zinc as well as a zinc reservoir that can be utilized when zinc is deficient. To examine the importance of MT for these processes, mice with null alleles of both MT I and MT II genes were created and the zinc concentration and histological appearance of multiple organs assessed. At birth, the hepatic zinc concentration of these MT-null mice was lower than that of wild-type controls (0.27 ± 0.02 vs. 0.65 ± 0.11 µmol zinc/g tissue, P < 0.05). During the next 3 wk of suckling zinc-replete (95 µg zinc/g diet) dams, the hepatic zinc concentration of controls fell to 0.42 ± 0.04 µmol/g but was unchanged in the MT-null mice (0.28 ± 0.04 µmol/g). The most prominent histological anomaly observed at 3 wk of age was the presence of swollen Bowman's capsules in the kidneys of MT-null mice. When nursing MT-null dams were fed a severely zinc-deficient (1.5 µg/g) diet, kidney development in the MT-null pups was retarded as indicated by the retention of the nephrogenic zone and incomplete tubule development. We suggest that the lack of a hepatic reservoir of zinc jeopardizes the developing kidney in the MT-null mice. In addition to being more sensitive to dietary zinc restriction, MT-null mice are more sensitive to zinc toxicity. When adult mice were challenged with a ramping dose of zinc up to a total of 3700 µmol zinc/kg body weight, MT-null mice had a greater incidence of pancreatic acinar cell degeneration compared with control mice despite accumulating less zinc (2.72 ± 0.46 vs. 1.23 ± 0.52 µmol zinc/g pancreas, control and MT-null, respectively, P < 0.05). The results of these experiments suggest that MT I and MT II can protect against both zinc deficiency and zinc toxicity.

KEY WORDS: • mice • metallothionein • zinc-deficiency • kidney • zinc toxicity

¹ Supported in part by National Institutes of Health grant CA-61268 to R. D. Palmiter. E. J. Kelly is supported by Public Health Service National Research Service Award T32 GM07270.

² The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact.

³ To whom correspondence should be addressed at Howard Hughes Medical Institute, University of Washington, Box 357370, Seattle, WA 98195-7370.

Manuscript received 30 October 1995. Revision accepted 29 March 1996.

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