CADMIUM TOXICITY AND DISTRIBUTION IN METALLOTHIONEIN-I AND METALLOTHIONEIN-II DEFICIENT TRANSGENIC MICE

To date, numerous correlative studies have implicated metallothionein in the detoxification of heavy metals and in the regulation of metal d istribution within an organism. In the present study cadmium-binding p roteins (metallothionein equivalents), cadmium acute toxicity, and cad mium distribution in tissues and subcellular fractions were compared i n metallothionein-I and -II deficient (MT-/-) mice and the parental st rain carrying intact metallothionein genes (M+/+) to determine if the absence of metallothionein altered any of these parameters. In an unin duced state, M-/- mice expressed lower levels of cadmium-binding prote ins relative to MT+/+ mice in several tissues. Administration of zinc enhanced the levels of cadmium-binding proteins in liver, small intest ine kidney, pancreas, and male sex organs, but not in cecum or brain o f MT+/+ mice compared to zinc pretreated M-/- mice. The cadmium LD50 w as similar for MT-/-, MT+/+, and zinc-pretreated MT-/- mice (15-17 mu mol CdCl2/kg body weight delivered ip). However, zinc-pretreated MT+/ mice had a cadmium LD50 of 58-63 mu mol CdCL2/kg body weight. Over tw o-thirds of cadmium was found in liver, cecum, small intestine, and ki dney in both MT+/+ and MT-/- mice; therefore, metallothionein levels d o not appear to play a major role in the tissue distribution of cadmiu m. However, after zinc pretreatment, MT+/+ mice accumulated more cadmi um in the liver and less in other tissues, whereas the amount of cadmi um 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. Th is difference was accentuated after zinc pretreatment. Together these results indicate that basal levels of metallothionein do not protect f rom the acute toxicity of a single ip cadmium challenge. Furthermore, it does not appear that the cytosolic compartmentalization of cadmium is correlated with reduced toxicity.