Oxidative inactivation of paraoxonase1, an antioxidant protein and its effect on antioxidant action

Su Duy Nguyen, Dai-Eun Sok
Free Radical Research 2003, 37 (12): 1319-30
Paraoxonase1 (PON1), one of antioxidant proteins to protect low density lipoprotein (LDL) from the oxidation, is known to lose its activity in the oxidative environment. Here, we attempted to elucidate the possible mechanisms for the oxidative inactivation of PON1, and to examine the capability of hydroxyl radicals-inactivated PON1 to prevent against LDL oxidation. Of various oxidative systems, the ascorbate/Cu2+ system was the most potent in inactivating the purified PON1 (PON1) as well as HDL-bound PON1 (HDL-PON1). In contrast to a limited inactivation by Fe2+ (2.0 microM), the inclusion of Cu2+ (0.1-1.0 microM) remarkably enhanced the inactivation of PON1 in the presence of ascorbate (0.5mM). A similar result was also obtained with the inactivation of HDL-PON1. The inactivation of PON1 by ascorbate/Cu2+ was pevented by catalase, but not general hydroxyl radical scavengers, supporting inactivation. In addition, Cu2+ alone inactivated PON1, either soluble or HDL-bound, by different mechanisms, concentration-dependent. Separately, there was a reverse relationship between the inactivation of PON1 and its preventive action against LDL oxidation during Cu2+-induced oxidation of LDL. Noteworthy, ascorbate/Cu2+-inactivated PON1, which was charaterized by the partial loss of histidine residues, expressed a lower protection against Cu2+-induced LDL oxidation, compared to native PON1. Based on these results, it is proposed that metal-catalyzed oxidation may be a primary factor to cause the decrease of HDL-associated PON1 activity under oxidative stress, and radicals-induced inactivation of PON1 may lead to the decrease in its antioxidant action against LDL oxidation.

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