Selective peroxynitrite scavenging activity of 3-methyl-1,2-cyclopentanedione from coffee extract

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Abstract
It has been known that reactive oxygen and nitrogen species such as nitric oxide (NO), superoxide radical (.O−2) and their byproduct peroxynitrite (ONOO−) induce cellular and tissue injury, ultimately resulting in several human diseases. In this study, we examined scavenging effects of 3‐methyl‐1,2‐cyclopentanedione (MCP) from coffee extract on the reactivity of those toxic molecules. MCP significantly inhibited both the oxidation of 2,7‐dichlorodihydrofluorescein diacetate (H2DCFDA) by reactive oxygen species (ROS) (mainly .O−2) from kidney homogenate (41% at 100 μM) and the generation of fluorescent 4,5‐diaminofluorescein (DAF‐2) by NO from sodium nitroprusside (IC50 (concn producing 50% inhibition), 63.8 μM). More potently, however, MCP suppressed the oxidation of dihydrorhodamine 123 (DHR 123) to fluorescent rhodamine 123 mediated by authentic ONOO− with an IC50 value of 3.3 μM. The neutralizing effect of the reactivity of ONOO− by MCP was due to electron donation, not nitration of the compound. Additionally, MCP also decreased ONOO− formation of nitrotyrosine adducts of glutathione (GSH) reductase, and consequently protected the enzyme activity of GSH reductase against decreasing by ONOO−, indicating that MCP may prevent ONOO−‐induced damage of GSH reductase. Furthermore, MCP only weakly suppressed NO production, which is one of the upstream sources of ONOO− in‐vivo, suggesting that NO production may be not a pharmacological target for MCP. Taken together, our results suggest that MCP may be regarded as a selective regulator of ONOO−‐mediated diseases via direct scavenging activity of ONOO−.