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J.Health Sci., 51(6), 728-730, 2005
Monomethylarsonous Acid Inhibits Endothelial Nitric Oxide Synthase Activity
Daigo Sumi, Keiko Taguchi, Yang Sun, Yasuhiro Shinkai, and Yoshito Kumagai*
Department of Environmental Medicine, Doctoral Programs in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1, Tenno-dai, Tsukuba, Ibaraki 305-8575, Japan
Inorganic arsenic undergoes extensive reduction and oxidative methylation in cells to yield a reactive metabolite of inorganic arsenic monomethylarsonous acid (MMAIII), 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 MMAIII on endothelial NO synthase (eNOS) activity. With the membrane fraction of bovine aortic endothelial cells (BAEC), it was found that MMAIII with an IC50 value of 2.1 mu M 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 MMAIII-induced inhibition of eNOS activity. This report is the first to suggest that MMAIII interacts with eNOS protein through presumably vicinal thiols, leading to decreased eNOS activity.
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