Discrepancy between the nephrotoxic potencies of cadmium-metallothionein and cadmium chloride and the renal concentration of cadmium in the proximal convoluted tubules.
Acute exposure to inorganic cadmium produces hepatotoxicity, but no renal injury. In contrast, chronic exposure to Cd produces nephrotoxic effects. However, a single injection of cadmium bound to metallothionein (CdMT) can produce nephrotoxicity similar to that seen with chronic exposure to Cd. It is generally thought that CdMT is nephrotoxic because more CdMT than CdCl2 distributes to the kidney. To test this hypothesis, the toxic effects and distribution of Cd were compared after iv injection of CdMT and CdCl2 to mice. CdMT increased urinary excretion of glucose, and protein indicating renal injury. This dysfunction occurred with dosages as low as 0.2 mg Cd/kg. In contrast, renal function was unaltered by CdCl2 administration, even at dosages as high as 3 mg Cd/kg. CdMT distributed almost exclusively to the kidney, whereas CdCl2 preferentially distributed to the liver. However, a high concentration of Cd was also found in the kidneys after CdCl2 administration. In fact, the renal Cd concentration after administration of a high but nonnephrotoxic dose of CdCl2 was equal to or higher than that obtained after injection of nephrotoxic doses of CdMT. Light microscopic autoradiography studies, using 0.3 mg Cd/kg as CdMT and 3 mg Cd/kg as CdCl2, indicated that Cd from CdMT preferentially distributed to the convoluted segments (S1 and S2) of the proximal tubules, whereas Cd from CdCl2 distributed equally to the various segments (convoluted and straight) of the proximal tubules. However, the concentration of Cd at the site of nephrotoxicity, the proximal convoluted tubules, was higher after CdCl2 than after CdMT administration. A higher Cd concentration in both apical and basal parts of the proximal cells was found after CdCl2 than after CdMT administration. Therefore, the reason why CdMT is nephrotoxic and CdCl2 is not nephrotoxic is not due to a higher concentration of Cd in the target cells after CdMT than after CdCl2 administration.
Department of Pharmacology, University of Kansas Medical Center, Kansas City 66160-7417.
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Dorian
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Gattone
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Klaassen
D000704:Analysis of Variance; D000818:Animals; D001345:Autoradiography; D002104:Cadmium / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity*; D019256:Cadmium Chloride; D002712:Chlorides / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D006029:Glycosuria; D007275:Injections, Intravenous; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008668:Metallothionein / Q000008:administration & dosage / Q000633:toxicity*; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D016707:Tissue Fixation
D002712:Chlorides; C004203:cadmium-binding protein; D002104:Cadmium; D008668:Metallothionein; D019256:Cadmium Chloride