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The paraoxonase family consists of three members (PON1, PON2 and PON3) that share structural properties and enzymatic activities, among which is the ability to hydrolyze oxidized lipids in LDL. The exact function of the different family members is not clear although the conservation among the individual family members across species suggests a strong evolutionary pressure to preserve these functional differences. The purpose of this review is to highlight several problems with respect to the mechanism of action of paraoxonase and differences between the family members that merit further study.PON1 transgenic mice are at lower risk for atherosclerosis, which is consistent with PON1 gene knockout studies in mice and human genetic polymorphism studies. The exact mechanism by which paraoxonase is cardioprotective is not clear, although it is likely to be related to its antioxidant properties especially on LDL. PON1 levels are influenced by a variety of environmental factors, including statins and cytokines. The preferential association of PON1 with HDL is mediated in part by its signal peptide and by desorption from the plasma membrane of expressing cells by HDL or phospholipid. Apolipoprotein A-I is not necessary for PON1 association with HDL, but its activity is stabilized in the presence of the apolipoprotein. Only in the absence of both lecithin cholesterol acyltransferase and apolipoprotein E is paraoxonase associated with non-HDL lipoproteins. The displacement of paraoxonase by serum amyloid A may explain in part the proinflammatory nature of HDL in the acute phase. The mechanism by which PON3 associates with HDL has not been studied. In addition to the ability to hydrolyze oxidized lipids in LDL, paraoxonase also alters the oxidative state of macrophages. Exogenous PON1 is able to reverse the oxidative stress in macrophages in aged apolipoprotein E deficient and PON1 deficient mice. The increase in oxidative stress in macrophages from PON1 deficient mice occurs despite the expression of PON2 and PON3 in macrophages. PON1 has recently been shown to contain phospholipase A2 activity, with the subsequent release of lysophosphatidylcholine that influences macrophage cholesterol biosynthesis.PON1 mass and activity in the plasma significantly influence the risk of developing cardiovascular disease. This is likely mediated by its antioxidation properties on LDL and/or macrophages. The precise mechanism by which this HDL associated protein prevents or attenuates oxidation of LDL and the oxidative stress of macrophages remains to be clarified. The role of PON2 and PON3 in atherosclerosis and their antioxidant properties with respect to LDL and macrophages also merit further investigation.