Human serum paraoxonase (PON1) associated with high density lipoprotein (HDL) has been postulated to have a role in protecting low density lipoprotein (LDL) against oxidative modification, which has led to the proposal that PON1 is an antiatherogenic, anti-inflammatory enzyme. PON1 has two genetically determined polymorphic sites giving rise to amino-acid substitutions at positions 55 (LC CM) and 192 (RC CQ) and therefore 4 potential alloenzymes. We have examined the effects of these molecular polymorphisms on the ability of HDL to protect LDL from oxidative modification. HDL protected LDL from oxidative modification, whatever the combination of PON1 alloenzymes present in it. However, HDL from QQ/MM homozygotes was most effective at protecting LDL while HDL from RR/LL homozygotes was least effective. Thus after 6 h of co-incubation of HDL and LDL with Cu P+

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Abstract-Human serum paraoxonase (PON1) hydrolyzes oxidized lipids in low density lipoprotein (LDL) and could therefore retard the development of atherosclerosis. In keeping with this hypothesis, several case-control studies have shown a relationship between the presence of coronary heart disease (CHD) and polymorphisms at amino acid positions 55 and 192 of PON1, which we associated with a decreased capacity of PON1 to protect LDL against the accumulation of lipid peroxides, but some other studies have not. However, the PON1 polymorphisms are only 1 factor in determining the activity and concentration of the enzyme. Only 3 of the previous 18 studies directly determined PON1 activity and concentration. Therefore, we studied PON1 activity, concentration, and gene distribution in 417 subjects with angiographically proven CHD and in 282 control subjects. We found that PON1 activity and concentration were significantly lower in subjects with CHD than in control subjects (activity to paraoxon 122. Key Words: paraoxonase Ⅲ oxidation Ⅲ coronary heart disease Ⅲ genetic polymorphisms P araoxonase (EC.3.1.8.1, aryldialkylphosphatase) has been extensively studied in the field of toxicology. 1,2 Paraoxonase hydrolyzes organophosphate compounds, which are widely used as insecticides and nerve gases. 3,4 Human serum paraoxonase (PON1) is synthesized in the liver and is physically associated with HDL, on which it is almost exclusively located. The serum concentration of HDL has long been known to have an inverse correlation with the development of atherosclerosis. 5 The mechanism by which HDL renders its protective effect against atherosclerosis continues to be the subject of considerable debate. The initial focus of attention was on the role of HDL in reverse-cholesterol transport. However, recent studies have suggested more diversity in the role of HDL in atherogenesis. Several laboratories have reported that HDL protects against LDL oxidative modification, 6 -9 which is believed to be central to the initiation and progression of atherosclerosis. 10 We have previously shown that the antioxidant activity of HDL may relate, at least in part, to the enzymes associated with HDL. 11 Further studies have indicated that PON1 can prevent lipid peroxide accumulation on LDL in vitro and in vivo. [12][13][14] Studies have shown that serum PON1 activity is reduced in diabetes and familial hypercholesterolemia, 15,16 diseases that are associated with accelerated atherogenesis. PON1 activity is in part genetically determined. In this regard, most investigations have focused on an amino acid substitution at position 192 (Q3 R), giving rise to 2 allozymes. 3,17,18 This PON1 activity polymorphism is substrate dependent. Some substrates, such as paraoxon and fenitroxon, are hydrolyzed faster by the R allozyme, whereas other substrates, such as phenyl acetate, are hydrolyzed at the same rate by both allozymes, and yet others, such as diazoxon and the nerve gases soman and sarin, are hydrolyzed more rapidly by the Q allozyme. 19 A second polymor...