Mitochondrial reduction of the carcinogen chromate: formation of chromium(V)

Incubation of chromate with isolated rat liver mitochondria in vitro resulted in the uptake and reduction of chromium(VI), as well as the formation of chromium(V) species. Chromate was rapidly taken up and reduced by intact mitochondria. The rate of reduction of chromate by intact mitochondria was increased upon addition of succinate or malate plus glutamate, substrates for the electron-transport chain, but was decreased upon addition of cyanide, an inhibitor of the electron-transport chain. Incubation of chromate with mitochondria in the presence or absence of malate, glutamate, and succinate resulted in a steady increase in the level of chromium(V) over time. The extent of chromium(V) formation was increased upon addition of malate, glutamate, and succinate but was inhibited upon addition of the electron-transport chain inhibitors, antimycin, cyanide, or rotenone, to whole mitochondria. High levels of glutamate plus malate inhibited chromium(V) formation; however, high concentrations of succinate or sulfate had no effect. These studies suggest that the chromate-reductase activity in mitochondria is due to the electron-transport chain as well as other mitochondrial reducing systems which are insensitive to inhibitors of the electron-transport chain. Since chromium(VI) is effectively metabolized by mitochondria in vitro and chromium(V) "reactive intermediates" are formed in the process, mitochondria may play a role in chromium(VI) carcinogenesis.