Metallothionein plays less of a protective role in cadmium- metallothionein-induced nephrotoxicity than in cadmium chloride-induced hepatotoxicity

J Liu, Y Liu, AE Michalska, KH Choo and CD Klaassen

Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA.

Metallothioneins (MTs) are low-molecular weight, cysteine-rich, metal- binding proteins. Pretreatment of animals with Zn increases tissue MT concentrations, and protects against Cd-induced toxicity. However, Zn treatment produces many effects in addition to increasing MT. Therefore, MT-I and -II knock-out (MT-null) mice were used to determine the roles of MT in Cd-induced hepatotoxicity and nephrotoxicity, as well as in Zn-induced protection. MT-null mice were more sensitive to CdCl2 (25 mumol/kg i.p.) hepatotoxicity, as evidenced by 25-fold increases in serum alanine aminotransferase activity, compared to 12- fold increases in control mice. Zn pretreatment (200 mumol/kg s.c. x 2 days) increased hepatic MT 80 fold in control mice but not in MT-null mice, and prevented CdCl2 hepatotoxicity in control mice only. It is concluded that MT plays a critical role in Cd-induced hepatotoxicity. In contrast to CdCl2-induced hepatotoxicity, MT-null mice were equally susceptible as controls to the Cd-MT (CdMT) (0.1-0.4 mg Cd/kg i.v.) nephrotoxicity, as evidenced by similar increases in urinary protein (up to 30-fold) and glucose excretion (up to 60-fold), as well as similar extent of proximal tubular necrosis. Zn increased renal MT (28- fold) in control mice only; however, it protected against CdMT-induced renal injury in both control and MT-null mice. These findings suggest that MT plays less of a protective role in protecting against CdMT- induced nephrotoxicity than CdCl2-induced hepatotoxicity, and that Zn- induced protection against CdMT-induced nephrotoxicity does not appear to be mediated through MT.

Volume 276, Issue 3, pp. 1216-1223, 03/01/1996
Copyright © 1996 by American Society for Pharmacology and Experimental Therapeutics

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