Cadmium hepatotoxicity and alterations of the mitochondrial function

OBJECTIVE: To examine the effect of low concentrations of cadmium on isolated liver mitochondrial function as related to hepatotoxicity. METHODS: Tetraphenyl phosphonium ion uptake and retention, estimated with a tetraphenyl phosphonium-sensitive electrode, was used to monitor changes in liver inner mitochondrial membrane potential. Ca2+ efflux was measured spectrophotometrically with the Ca2+ indicator Arsenazo III. Mitochondrial swelling was measured spectrophotometrically at 540 nm. Oxygen consumption was measured with a Clark-type oxygen microelectrode. RESULTS: Incubation of isolated liver mitochondria with cadmium (5-30 microM) altered mitochondrial function as indicated by swelling, inhibition of respiration, loss of inner mitochondrial membrane potential, and loss of preaccumulated Ca2+. The presence of dithiothreitol (2 mM) in the incubation medium restored mitochondrial function to almost the control level. Cyclosporin A (1 microM), however, did not provide any protection against cadmium toxicity. CONCLUSIONS: The findings point to a direct effect of cadmium on liver mitochondrial function. Cadmium toxicity may be due to loss of reduced glutathione rather than to increased mitochondrial inner membrane permeability. The effect of cadmium on liver mitochondria seems to be an early event in cadmium-induced hepatotoxicity.