To date, numerous correlative studies have implicated metallothionein in the detoxification of heavy metals and in the regulation of metal distribution within an organism. In the pre sent study cadmium-binding proteins (metallothionein equivalents), cadmium acute toxicity, and cadmium distribution in tissues and subcellular fractions were compared in metalloth-ionein-l and -II deficient (MT−/−) mice and the parental strain carrying intact metalloth ionein genes (MT+/+) to determine if the absence of metallothionein altered any of these parameters. In an uninduced state, MT−/−mice expressed lower levels of cadmium-binding proteins relative to MT+/+mice in several tissues. Administration of zinc enhanced the levels of cadmium-binding proteins in liver, small intestine, kidney, pancreas, and male sex organs, but not in cecum or brain of MT+/+mice compared to zinc pretreated MT−/−mice. The cadmium LD50 was similar for MT−/−, MT+/+, and zinc-pretreated MT−/−mice (15-17To date, numerous correlative studies have implicated metallothionein in the detoxification of heavy metals and in the regulation of metal distribution within an organism. In the pre sent study cadmium-binding proteins (metallothionein equivalents), cadmium acute toxicity, and cadmium distribution in tissues and subcellular fractions were compared in metalloth-ionein-l and -II deficient (MT−/−) mice and the parental strain carrying intact metalloth ionein genes (MT+/+) to determine if the absence of metallothionein altered any of these parameters. In an uninduced state, MT−/−mice expressed lower levels of cadmium-binding proteins relative to MT+/+mice in several tissues. Administration of zinc enhanced the levels of cadmium-binding proteins in liver, small intestine, kidney, pancreas, and male sex organs, but not in cecum or brain of MT+/+mice compared to zinc pretreated MT−/−mice. The cadmium LD50 was similar for MT−/−, MT+/+, and zinc-pretreated MT−/−mice (15-17 μmol CdCl2/kg body weight delivered ip). However, zinc-pretreated MT+/+mice had a cadmium LD50 of 58-63 μmol CdCIJkg body weight. Over two-thirds of cadmium was found in liver, cecum, small intestine, and kidney in both MT+/+and MT−/−mice; therefore, metallothionein levels do not appear to play a major role in the tissue distribution of cad mium. However, after zinc pretreatment, MT+/+mice accumulated more cadmium in the liver and less in other tissues, whereas the amount of cadmium in the liver was not altered by zinc pretreatment in MT−/−mice. In general, the cytosolic/particulate ratio of cadmium was significantly higher in tissues of noninduced MT+/+mice relative to MT−/−mice. This difference was accentuated after zinc pretreatment. Together these results indi cate that basal levels of metallothionein do not protect from the acute toxicity of a single ip cadmium challenge. Furthermore, it does not appear that the cytosolic compartmental-ization of cadmium is correlated with reduced toxicity.