title: Cadmium toxicity and distribution in metallothionein-I and -II deficient transgenic mice.
abstract: 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 present study cadmium-binding proteins (metallothionein equivalents), cadmium acute toxicity, and cadmium distribution in tissues and subcellular fractions were compared in metallothionein-I and -II deficient (MT-/-) mice and the parental strain carrying intact metallothionein 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 mumol CdCl2/kg body weight delivered i.p.). However, zinc-pretreated MT+/+ mice had a cadmium LD50 of 58-63 mumol CdCl2/kg 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 cadmium. 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 indicate that basal levels of metallothionein do not protect from the acute toxicity of a single i.p. cadmium challenge. Furthermore, it does not appear that the cytosolic compartmentalization of cadmium is correlated with reduced toxicity.
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio 78284-7762, USA.
authors.forename: C C
authors.initials: CC
authors.lastname: Conrad
authors.forename: C A
authors.initials: CA
authors.lastname: Walter
authors.forename: A
authors.initials: A
authors.lastname: Richardson
authors.forename: M A
authors.initials: MA
authors.lastname: Hanes
authors.forename: D T
authors.initials: DT
authors.lastname: Grabowski
mesh_terms: D000818:Animals; D002104:Cadmium / Q000493:pharmacokinetics* / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D007928:Lethal Dose 50; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism; D008297:Male; D008668:Metallothionein / Q000096:biosynthesis / Q000172:deficiency* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D010088:Oxidoreductases / Q000097:blood; D013347:Subcellular Fractions / Q000378:metabolism; D014018:Tissue Distribution; D015032:Zinc / Q000494:pharmacology
chemical_list: C004203:cadmium-binding protein; D002104:Cadmium; D008668:Metallothionein; D010088:Oxidoreductases; D015032:Zinc