PON1 Paraoxonase Activity is Reduced During HDL Oxidation and is an Indicator of HDL Antioxidant Capacity

Abstract

The aim of this study was to investigate the effect of HDL oxidation on PON1 paraoxonase activity. Also, we were interested in investigating the mechanism by which PON1 could be inactivated and the correlation between its enzymatic activity and the antioxidant properties of HDL. Three different oxidation systems were used for the HDL oxidation: (1) oxidation induced by THP1 cells, (2) oxidation induced by copper ions at a concentration 10 microM, and (3) oxidation induced by *OH and O2.- oxygen free radicals produced by gamma-radiolysis. HDL oxidation was followed by the measurement of lipid peroxide formation, and PON1 activity was determined by measuring the rate of paraoxon hydrolysis. Our results show that HDL oxidation is accompanied by a reduction in the PON1 paraoxonase activity. The extent of PON1 inactivation depends both on the extent of HDL oxidation and on the oxidation system used. The rates of HDL oxidation and PON1 inactivation were significantly correlated (r = 0.93, p < 0.0054). Our results show that oxidized HDL loses its protective effect toward LDL oxidation. The antioxidant action of HDL towards LDL oxidation and the degradation of PON1 paraoxonase activity were significantly correlated (r = 0.95, p < 0.04).

Functionally Defective High-Density Lipoprotein: A New Therapeutic Target at the Crossroads of Dyslipidemia, Inflammation, and Atherosclerosis

“…5) Van Lenten et al, 2001b). Furthermore, decreased PON1 activity may be caused by enzyme inactivation as a result of oxidation (Jaouad et al, 2003) and/or glycation (Hedrick et al, 2000;Ferretti et al, 2001). Consistent with these observations, serum concentrations of PON1 are decreased in subjects with MetS (Blatter Garin et al, 2005) and in patients with type 1 and type 2 diabetes (Boemi et al, 2001;Costa et al, 2005), who feature elevated levels of inflammation and oxidative stress (Ridker et al, 2004a).…”

Preferential inhibition of paraoxonase activity of human paraoxonase 1 by negatively charged lipids

“…There are two possible mechanisms for the substrate-dependent alteration of PON1 activity: one is that PON1, modified by acquired factors such as reactive oxygen species or reactive aldehydes, may distinguish between two substrates, phenyl acetate and paraoxon; the other is that paraoxonase and arylesterase activities may be discriminated by endogenous inhibitors, which are present in the HDL particle or se- rum sample. Earlier studies have shown that PON1 could be inactivated by endogenously generated oxidants (12,14,31,32,48). In the present study, however, the differential substrate recognition was not addressed by any PON1 molecules modified by the oxidants except HOCl, which caused a greater reduction of arylesterase activity than paraoxonase activity.…”

“…Concerning the oxidative inactivation of PON1, it has been shown that PON1 activity was reduced during exposure to oxidized LDL or reactive oxygen species (28)(29)(30)(31)(32). Additionally, 4-hydroxy-2-nonenal, which gradually accumulates in the later stage of LDL oxidation, can also cause the inactivation of PON1 arylesterase activity (32).…”

A review of paraoxonase 1 properties and diagnostic applications

“…There are several reports about oxidative inactivation of paraoxonase (Cao et al 1999, Jaouad et al 2003.…”