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

Abstract

To determine the causes responsible for a preferential decrease of paraoxonase activity, which has been observed in the serum of patients with cardiovascular diseases, the inactivation or inhibition of paraoxonase 1 (PON1) by various endogenous factors was examined using paraoxon or phenyl acetate as a substrate. When purified PON1 was incubated with various endogenous oxidants or aldehydes, they failed to cause a preferential reduction of paraoxonase activity, suggesting no participation of the inactivation mechanism in the preferential loss of paraoxonase activity. Next, when we examined the inhibition of PON1 activity by endogenous lipids, monoenoic acids such as palmitoleic acid or oleic acid inhibited paraoxonase activity preferentially, in contrast to a parallel inhibition of both activities by polyunsaturated or saturated acids. Noteworthy, oleoylglycine inhibited paraoxonase activity, but not arylesterase activity, complying with the selective inhibition of paraoxonase activity. Moreover, such a selective inhibition of paraoxonase activity was also expressed by lysophosphatidylglycerol or lysophosphatidylinositol, but not by lysophosphatidylserine or lysophosphatidylcholine, indicating the importance of the type of head group. Furthermore, such a preferential or selective inhibition of paraoxonase activity was also observed with PON1 associated with HDL or plasma. These data suggest that some negatively charged lipids may correspond to factors causing the preferential inhibition of paraoxonase activity of PON1.

Paraoxonases and cardiovascular diseases: pharmacological and nutritional influences

“…In contrast, an in-vitro study by Nguyen and Sok [65 ] showed that lysophosphatidylglycerol and lysophosphatidylinositol inhibited PON1 activity, whereas lysophosphatidylserine or lysophosphatidylcholine had no such effect, suggesting that endogenous lipids can affect PON1 activity, and their effect depends on the type of their head group. Finally, cholesterol supplementation in rats resulted in a significant decrease in hepatic PON1 synthesis, whereas it had no effect on other hepatic antioxidant enzyme activities [66].…”

Pharmacological and dietary modulators of paraoxonase 1 (PON1) activity and expression: The hunt goes on

“…In vitro studies have shown that oleic acid protects PON1 from oxidative inactivation, while polyenoic fatty acids inhibited PON1 activity [88]. However, oleic acid itself has also been shown to inhibit PON1 activity, possibly binding to a different site [89]. …”

Dietary fatty acid intake is associated with paraoxonase 1 activity in a cohort-based analysis of 1,548 subjects

“…Negatively charged lipids, including saturated, monounsaturated, and polyunsaturated DFAs, have all been reported to inhibit PON1 enzyme activity in vitro [23], with polyunsaturated fatty acids having the largest inhibitory effect [24]. However, monounsaturated fatty acids (and to a lesser extent, saturated fats) have also been shown to protect PON1 from ascorbate/copper-mediated oxidative inactivation [24,25].…”