Recurrence of toxicity by cadmium released from accumulated cadmium-metallothionein in mice

Cadmium (Cd) is a widespread toxic pollutant that enters humans and animals through the food chain. Cd usually is accumulated by binding to metallothionein (NIT), which appears to be responsible for its detoxification in the cell. To investigate whether the Cd released from Cd-MT can cause toxicity to recur, we studied the effects of oxidative stress and contamination with multiple metals on the release of Cd from accumulated Cd-MT and recurrence of toxicity in vitro and in vivo. Incubation of Cd-MT with H2O2, ferric nitrilotriacetate (Fe-NTA) and H2O2, or Cu2+ resulted in release of Cd from its binding with MT. In vivo study, Cd was released from renal Cd-MT after mice that bad accumulated Cd-MT were injected with Fe-NTA. Addition of purified Cd-MT to mouse liver cytosol did not result in inhibition of cytosolic superoxide dismutase (SOD) activity. However, treatment of CdNIT with H2O2 or Cu2+ led to the release of Cd2+ from Cd-MT, which inhibited cytosolic SOD activity. Simultaneous injection with Cu2+ and a non-acute toxic dose of Cd significantly increased plasma aminotransferase activities, indicating hepatic injury, in mice that had accumulated Cd-MT but not in those that had accumulated Zn-MT. The hepatic concentration of Cu increased with the injected dose and the concentration of Cd in the NIT fraction decreased. These results suggest that contamination with metals whose affinities for NIT are higher than that of Cd may cause recurrent toxicity due to the release of Cd from accumulated Cd-MT.