PROTECTION BY ZINC-METALLOTHIONEIN (ZNMT) AGAINST CADMIUM-METALLOTHIONEIN-INDUCED NEPHROTOXICITY

In contrast to inorganic Cd, acute iv administration of Cd bound to me tallothionein (CdMT) concentrates in renal tissue. This uptake of CdMT produces functional and morphological changes in kidneys, similar to those observed after chronic exposure to inorganic Cd. In order to exa mine the importance of the metal component of MT in the renal uptake o f MT, the renal concentration of S-35 after administration of [S-35]Zn MT and [S-35]CdMT was compared. Renal uptake of S-35 from both CdMT an d ZnMT was very rapid, with peak concentrations observed 15-30 min aft er administration. S-35 in kidneys increased in a dose-dependent manne r after administration of various doses of [S-35]ZnMT, up to 1.3 mu mo le MT/kg; however, higher doses did not further increase renal S-35 co ncentrations. A similar saturation of S-35 reabsorption was observed f or the renal uptake of [S-35]CdMT. CdMT produced renal injury with dos es as low as 0.26 mu mol MT/kg (0.2 mg Cd/kg). In contrast, with a dos e of ZnMT as high as 5.12 mu mol MT/kg (2 mg Zn/kg), no histopathologi cal changes were observed. Therefore, ZnMT appears to be nontoxic even though ZnMT delivers more MT to the kidney than does CdMT. Because Zn MT and CdMT are apparently handled by the same renal transport mechani sm, the effects of ZnMT on (109)CdMT renal uptake and nephrotoxicity w ere determined. One group of mice was given a nephrotoxic dose of (109 )CdMT (0.51 mu mol MT/kg containing 0.4 mg Cd/kg, iv), and the other g roup received an equimolar dose of unlabeled ZnMT 1 min before (109)Cd MT administration. Renal function was evaluated by measuring urinary g lucose and protein excretion, as well as histopathology. Marked renal toxicity was observed 24 hr after (109)CdMT administration. In contras t, renal function appeared normal in mice receiving ZnMT before (109)C dMT. However, a similar concentration of Cd-109 was found in kidneys o f both groups. The present results demonstrate that ZnMT is not only n ontoxic to the kidney at a dose as high as 5 mu mol MT/kg, but can als o protect against the nephrotoxic effect of CdMT without decreasing re nal Cd concentration. (C) 1995 Society of Toxicology.