METALLOTHIONEIN PLAYS LESS OF A PROTECTIVE ROLE IN CADMIUM-METALLOTHIONEIN-INDUCED NEPHROTOXICITY THAN IN CADMIUM CHLORIDE-INDUCED HEPATOTOXICITY

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. Therefor e, MT-I and-II knock-out (MT-null) mice were used to determine the rol es of MT in Cd-induced hepatotoxicity and nephrotoxicity, as well as i n Zn-induced protection. MT-null mice were more sensitive to CdCl2 (25 mu mol/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 mu mol/kg s.c. x 2 days) increa sed hepatic MT 80 fold in control mice but not in MT-null mice, and pr evented CdCl2 hepatotoxicity in control mice only. It is concluded tha t MT plays a critical role in Cd-induced hepatotoxicity. In contrast t o 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 p roximal tubular necrosis. Zn increased renal MT (28-fold) in control m ice only; however, it protected against CdMT-induced renal injury in b oth control and MT-null mice. These findings suggest that MT plays les s of a protective role in protecting against CdMT-induced nephrotoxici ty than CdCl2-induced hepatotoxicity, and that Zn-induced protection a gainst CdMT-induced nephrotoxicity does not appear to be mediated thro ugh MT.