A mechanism for cadmium- and zinc-induced tolerance to cadmium toxicity: Involvement of metallothionein

Abstract

Mouse-derived metallothionein was found to consist of two distinct cadmium-binding proteins possessing similar absorption and metal-binding properties. A sensitive technique for analyzing proteins, pulse polarography, was successfully employed for the analysis of metallothionein. Mice exhibited tolerance to Cd toxicity after pretreatment with either Cd or Zn acetate. Cd doses of 0, 1.0, and 3.2 mg/kg, 48 hr prior to Cd challenge, resulted in LD50 values of 4.5, 6.0, and 8.2 mg/kg, respectively. The hepatic metallothionein content increased with the pretreatment dose of cadmium. The LD50 values for cadmium were 5.7 and 10.3 mg/kg, respectively, for the control animals and for animals given three doses of 6.5 mg/kg of Zn at 12, 30, and 48 hr prior to the Cd challenge. Zn pretreatment induced formation of a Zn-binding protein the molecular weight of which appears to be identical with that of Cd-induced metallothionein. Cd-induced liver metallothionein contained Cd and Zn, whereas metallothionein resulting from Zn injections contained only Zn. Cd or Zn pretreatment of mice challenged with 10–12 mg of Cd/kg 3 hr prior to sacrifice resulted in an in vivo displacement by Cd of Zn from both Cd- and Zn-metallothionein. These results suggest that tolerance to Cd seen in pretreated mice is a result of the subsequent in vivo displacement of Zn from, and the chelation of Cd to, metallothionein. 14C-amino acid incorporation into liver metallothionein was found to be higher 12 hr after the administration of Cd than after 48 hr. The total amount of metallothionein protein in the liver at 48 hr was twice that found a 12 hr, whereas metallothionein-bound Cd was increased only slightly.