Copper ions and hypochlorite are mainly responsible for oxidative inactivation of paraoxon-hydrolyzing activity in human high density lipoprotein

Su Duy Nguyen, Ju Ryung Kim, Mee Ree Kim, Tae-Sook Jung, Dai-Eun Soka
Toxicology Letters 2004 March 7, 147 (3): 201-8
Paraoxon-hydrolyzing activity of HDL (HDL-PON1) is known to lose its activity under oxidative stress condition. Here, we attempted to elucidate the possible causes for the oxidative inactivation of HDL-PON1 in vivo system. Of various oxidative systems, ascorbate/Cu2+ system was the most potent in inactivating the paraoxon-hydrolyzing activity of purified PON1 (PON1). The inclusion of Cu2+ (0.5-2.0 microM) remarkably enhanced the ascorbate (0.5 mM)-induced inactivation of purified PON1. A similar inactivation was also obtained with HDL-PON1, although to a less extent. The inactivation of PON1, either purified or HDL-bound, by ascorbate/Cu2+ was prevented by catalase or thiols, but not general hydroxyl radical scavengers, suggesting the involvement of Cu(2+)-catalyzed oxidation in PON1 inactivation. In addition, some lipids such as oleic acid or dioleoylphophatidylglycerol expressed a partial protection. Noteworthy, HDL-PON1, but not purified PON1, was inactivated significantly in a concentration-dependent manner by Cu2+ alone, and the inactivation of HDL-PON1 by Cu2+ was prevented by catalase, consistent with the intermediacy of H2O2 in Cu(2+)-induced inactivation of HDL-PON1. Separately, PON1, either purified or HDL-bound, was found to be susceptible to hypochlorite oxidation. While the susceptibility to hypochlorite below 1 mM was similar between purified PON1 and HDL-PON1, the inactivation of HDL-PON1 by hypochlorite at > 1 mM seemed to be interfered by the membrane. Moreover, the sequential inclusion of hypochlorite and ascorbate/Cu2+ showed a cooperative action in inactivating HDL-PONI. Based on these results, it is proposed that copper ion-catalyzed oxidation and hypochlorite oxidation may be mainly responsible for the loss of HDL-associated paraoxonasel activity.

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