Iron stimulates the rate of reduction of hexavalent chromium by human microsomes.
The NADPH-dependent reduction of chromium (VI), a known carcinogen, by hepatic microsomes was very similar for all five humans examined, with an apparent Km for chromate of 1.04-1.68 microM, and a Vmax of 10.4-10.7 nmol/min/mg protein. Inhibitor studies indicate no role for cytochrome P450s, but a prominent role for flavoproteins, which could include P450 reductase, flavin-containing mono-oxygenase and cytochrome b5. Relative to anaerobic conditions, Cr(VI) reduction was inhibited only 26-37% by room air, which indicates that human microsomal Cr(VI) reduction could still proceed at significant rates, even in tissues with high O2 tensions. Studies with lung microsomes from one human exhibited Vmax and Km values that were two-thirds lower and 2.8-fold greater, respectively, than those of hepatic microsomes from the same individual; other Cr(VI)-reducing parameters were similar for lung and liver. Various forms of exogenous iron, when present at 0.76-6.3 microM, markedly enhanced both liver and lung microsomal rates and Vmax of Cr(VI) reduction, but did not significantly alter the other Cr(VI)-reducing parameters (Km, effects of O2 and inhibitors). These iron levels were 3.1- to 26-fold lower than the initial Cr(VI) concentration, which suggests that iron is serving a catalytic role. The ratio of human microsomal Cr(VI) reduction rates under aerobic versus anaerobic conditions remained fairly constant, regardless of iron concentration. Small increases in intracellular iron could therefore lead to large increases in the rate and extent of microsomal Cr(VI) reduction. Individuals that are simultaneously exposed to Cr(VI) and to agents that increase intracellular iron could therefore be at potentially greater risk for Cr(VI) toxicity and carcinogenicity.
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee 53226, USA.
C R
CR
Myers
J M
JM
Myers
D000328:Adult; D002274:Carcinogens, Environmental / Q000493:pharmacokinetics*; D002857:Chromium / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007501:Iron / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000378:metabolism*; D008875:Middle Aged; D010084:Oxidation-Reduction
D002274:Carcinogens, Environmental; D002857:Chromium; C074702:chromium hexavalent ion; D007501:Iron