Monomethylarsonous Acid Inhibits Endothelial Nitric Oxide Synthase Activity

概要

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Inorganic arsenic undergoes extensive reduction and oxidative methylation in cells to yield a reactive metabolite of inorganic arsenic monomethylarsonous acid (MMA^<III>), which has a high reactivity toward vicinal thiols. Our epidemiological study in an endemic area of chronic arsenic poisoning and in experiments with rabbits exposed to arsenic revealed that arsenic exposure results in a reduction of systemic nitric oxide (NO) production. In this study, we examined the effect of MMA^<III> on endothelial NO synthase (eNOS) activity. With the membrane fraction of bovine aortic endothelial cells (BAEC), it was found that MMA^<III> with an IC_<50> value of 2.1μM was a potent inhibitor of eNOS, whereas inorganic arsenic and their methylated metabolites had no effect on eNOS activity. Interestingly, addition of dithiothreitol markedly blocked the MMA^<III>-induced inhibition of eNOS activity. This report is the first to suggest that MMA^<III> interacts with eNOS protein through presumably vicinal thiols, leading to decreased eNOS activity.
公益社団法人日本薬学会の論文
2005-12-01