Chromium Toxicity: Reductive Activation by Human Enzymes

摘要

Chromium(VI) reduction by human lung is similar to that in liver, with significant rates of reduction using chromium(VI) concentrations anticipated for occupational exposure. The lung results are consistent with a prominent role for cytochrome b5 in cooperation with NADPH:P450 reductase or NADH:b5 reductase as principal mediators of Cr(VI) reduction. There is little interindividual difference in Cr(VI) reduction catalyzed by lung microsomes. During Cr(VI) reduction, the reactive intermediate Cr(V) appears early and is generated over a long period of time. Cr(IV) and Cr(III) appear later in the time courses, suggesting a series of consecutive one-electron reductions: Cr(VI) ---> Cr(V) ---> Cr(IV) ---> Cr(III). Similar to iron, small amounts of certain redox-active quinones can markedly stimulate microsomal Cr(VI) reduction, causing a more rapid reduction of both Cr(VI) and Cr(V). Individuals who are simultaneously exposed to chromium and quinones, which are ubiquitous environmental pollutants, are therefore likely at greater risk for chromium toxicity. The effect of quinones under aerobic conditions was influenced by the quinone itself, the quinone concentration, and the ratio of O2 to Cr(VI). Other redox active compounds (methyl viologen, azobenzene, and 2,4- dinitrophenylhydrazine) cause little or no stimulation of Cr(VI) reduction. Human cytochrome P450s do not contribute to the quinone effect; the quinones are likely reduced by cytochrome b5 in cooperation with NADPH:P450 reductase or NADH:b5 reductase.