This Article Abstract Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Durrington, P. N. Articles by Mackness, M. I. Search for Related Content PubMed PubMed Citation Articles by Durrington, P. N. Articles by Mackness, M. I. Related Collections Pathophysiology Genetics of cardiovascular disease Lipid and lipoprotein metabolism Oxidant stress

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:473.)
© 2001 American Heart Association, Inc.

Brief Review

Paraoxonase and Atherosclerosis

P. N. Durrington; B. Mackness; M. I. Mackness

From the University of Manchester Department of Medicine, Manchester Royal Infirmary, Manchester, England.

Correspondence to Prof P.N. Durrington, University of Manchester Department of Medicine, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, England. E-mail pdurrington{at}hq.cmht.nwest.nhs.uk

	Abstract

Top Abstract Introduction Antioxidant Role of HDL PON1 and Other Enzymatic... Sources of Variation in... PON1 and Atherosclerosis Potential for Modifying Serum... Other Diseases Associated With... Conclusion References

 
Abstract—There is considerable evidence that the antioxidant activity of high density lipoprotein (HDL) is largely due to the paraoxonase-1 (PON1) located on it. Experiments with transgenic PON1 knockout mice indicate the potential for PON1 to protect against atherogenesis. This protective effect of HDL against low density lipoprotein (LDL) lipid peroxidation is maintained longer than is the protective effect of antioxidant vitamins and could thus be more important. There is evidence that the genetic polymorphisms of PON1 least able to protect LDL against lipid peroxidation are overrepresented in coronary heart disease, particularly in association with diabetes. However, these polymorphisms explain only part of the variation in serum PON1 activity; thus, a more critical test of the hypothesis is likely to be whether low serum PON1 activity is associated with coronary heart disease. Preliminary case-control evidence suggests that this is indeed the case and, thus, that the quest for dietary and pharmacological means of modifying serum PON1 activity may allow the oxidant model of atherosclerosis to be tested in clinical trials.

Key Words: paraoxonase • lipid peroxidation • high density lipoproteins

	Introduction

Top Abstract Introduction Antioxidant Role of HDL PON1 and Other Enzymatic... Sources of Variation in... PON1 and Atherosclerosis Potential for Modifying Serum... Other Diseases Associated With... Conclusion References

 
Paraoxonase-1 (PON1) is a protein of 354 amino acids with a molecular mass of 43 kDa.^{1 2} In serum, it is almost exclusively located on HDL. It is highly conserved in mammals but is absent in fish, birds, and invertebrates, such as arthropods. PON1 can bind reversibly to organophosphate substrates, which it hydrolyzes. In contrast, organophosphates are suicide substrates for other serum organic esterases, such as pseudocholinesterase, and for the acetylcholinesterase at synapses and the neuromuscular junction, because they bind irreversibly to them. PON1 is thus the main means of protection of the nervous system against the neurotoxicity of organophosphates entering the circulation. It was in this context that it was first discovered, and its name reflects its ability to hydrolyze paraoxon, a metabolite of the insecticide parathion. There is wide interindividual variation in the capacity of PON1 to hydrolyze organophosphates and other organic esters.

The PON1 gene is located on the long arm of chromosome 7 between q21.3 and q22.1 with other members of its supergene family.^{3 4} Next to the PON1 gene is a gene that codes for 1 of the pyruvate dehydrogenase kinases⁵ and may explain the linkage of paraoxonase (PON) genotypes with diabetic glycemic control in some studies.^{6 7} The product of PON2 has not yet been identified in biological tissue, but the PON3 gene product has recently been identified as a lactonase located on rabbit HDL.⁸

PON1 has recently emerged as the component of HDL most likely to explain its ability to metabolize lipid peroxides and to protect against their accumulation on LDL. The present review will consider first the antioxidant role of HDL in the context of its other potential antiatherogenic actions and then the evidence that PON1 is indeed responsible for the capacity of HDL to metabolize lipid peroxides before finally discussing the evidence that PON1 is linked with clinically evident atherosclerosis.

	Antioxidant Role of HDL

Top Abstract Introduction Antioxidant Role of HDL PON1 and Other Enzymatic... Sources of Variation in... PON1 and Atherosclerosis Potential for Modifying Serum... Other Diseases Associated With... Conclusion References

 
There does not appear to be any single explanation for the inverse relationship between serum HDL and risk of atherosclerosis. For much of the time that this relationship has been known, attention has focused on the concept that HDL might be rate limiting for reverse cholesterol transport. However, evidence to support this view remains incomplete.⁹ Rabbits expressing multiple copies of the human apoA-I gene or receiving infusions of human apoA-I can be protected against experimental diet-induced atherosclerosis,^{10 11} but the levels of circulating apoA-I required to achieve this are greatly in excess of the variation seen in humans. When only 2 copies of the human apoA-I gene are expressed in rabbits (even so, more than doubling their HDL cholesterol concentration), they are not protected against atherosclerosis.¹² Furthermore, apoA-I knockout mice are not rendered prone to atherosclerosis.¹³ Recent evidence concerning the cause of Tangier disease (analphalipoproteinemia) does not suggest that the profound defect in reverse cholesterol transport associated with the condition is the consequence of the low circulating HDL but rather that its cause is mutation of the ATP binding cassette-1 transporter gene, with the low HDL representing a secondary effect of diminished cellular cholesterol efflux.^{14 15 16 17 18}

Evidence is strong that low HDL cholesterol is a marker for the presence of a small, dense, cholesterol-depleted LDL in the circulation, which itself increases the risk of atherosclerosis, probably because of its susceptibility to oxidation.¹⁹ Low HDL may be linked with the generation of this type of LDL through the increased triglyceride pool that is also often present, because lipoprotein lipase activity, which is necessary to generate HDL components from triglyceride-rich lipoproteins and to catabolize them, is frequently diminished.^{20 21} Additionally, enhanced cholesteryl ester transfer protein activity and increased hepatic lipase activity, which are also linked with the generation of small LDL, contribute to its association with low HDL cholesterol. This is because cholesteryl ester transfer protein promotes the movement of cholesteryl ester out of HDL, and hepatic lipase can increase the hepatic uptake of HDL lipids.^{22 23 24} Again, however, the low circulating HDL cholesterol is itself simply a marker of these other metabolic processes and does not itself directly accelerate atherogenesis.

Seeking to find a more direct link between HDL and atherogenesis and with the growing evidence that the oxidation of LDL is a major factor in human atherosclerosis,²⁵ we hypothesized that HDL might directly protect LDL against oxidative modification. At the time, it had been reported that HDL could protect endothelial cells against the cytotoxic effects of LDL²⁶ and that the extent of LDL lipid peroxidation was less when HDL was present.²⁷ This latter observation was at first attributed to lipid peroxides transferring from LDL to HDL.²⁷ Although this undoubtedly does occur and could assist in protecting LDL against oxidative damage, we convincingly demonstrated that the total quantity of lipid peroxides formed when LDL and HDL were incubated together under oxidizing conditions was less than the total quantity of lipid peroxides formed when LDL and HDL were incubated separately under similar conditions.²⁸ Furthermore, the accumulation of lipid peroxides on HDL was similar regardless of whether LDL was present, whereas that on LDL was decreased in the presence of HDL (Figure 1). This has subsequently been confirmed.^{29 30 31 32 33} The most likely mechanism by which HDL diminished lipid peroxide accumulation was an enzymatic hydrolysis of phospholipid hydroperoxides.²⁹ The LDL lipids most susceptible to oxidation are polyunsaturated phospholipids, such as phosphatidylcholine with a polyunsaturated fatty acyl group in the Sn2 position. In human LDL, this group is most likely to be linoleate. The most susceptible site for hydrogen abstraction and peroxidation by oxygen-derived free radicals would then be the double bond at carbon 9 in the hydrocarbon chain of the linoleate group. HDL probably catalyzes hydrolysis of the hydroperoxide at this site, releasing a carbon 9 fragment. HDL also has the capacity to remove by hydrolysis the carbon 9 fatty acid remaining at the Sn2 position of phosphatidylcholine and, thus, to leave lysolecithin.³⁴ Of course, carbon 9 aldehydes or ketones spontaneously released from the linoleate hydroperoxide are what are believed to adduct covalently to amino acids of apoB, leading to its fragmentation and recognition by scavenger and other oxidized LDL receptors.³⁵ However, the rapid enzymatic release of these fragments on HDL rather than LDL appears to protect apoB.³⁶ The lysolecithin released by the action of HDL is also potentially cytotoxic. Again, however, its release on HDL is not apparently damaging. That HDL is a safe place to release lysolecithin is also strongly suggested by the huge quantities, which are known to be released there physiologically by the action of lecithin-cholesterol acyltransferase (LCAT), located on HDL. In the human, this is the main mechanism by which plasma cholesterol is esterified, including most of that newly synthesized and secreted into the circulation by the liver.³⁷ There are numerous studies showing that HDL prevents the uptake of LDL by macrophages and other cells and reduces the cytotoxicity, which would occur under similar oxidizing conditions in the absence of HDL.^{26 27 30 31} In addition to glycerophospholipid peroxides, PON1 also metabolizes peroxides of cholesteryl esters.³² The PON3 protein recently isolated from rabbit serum was also shown to diminish lipid peroxide accumulation on LDL.⁸

View larger version (19K): [in this window] [in a new window]   Figure 1. Lipid peroxide accumulation on LDL and HDL incubated under oxidizing conditions singly and together.29 *P<0.05 and **P<0.001 vs LDL incubated alone.

The oxidant hypothesis of atherosclerosis has thus far been tested in clinical trials by attempting to increase the fat-soluble antioxidant vitamins present in lipoproteins, and results have been generally disappointing.³⁸ However, the protection that the fat-soluble antioxidants afford LDL against lipid peroxidation is short-lived. The lag phase in conjugated diene formation, which occurs early in LDL oxidation, is the phase most clearly prolonged by fat-soluble antioxidants, but even large doses extend it only briefly, with no effect on the subsequent generation of lipid peroxides²⁹ (Table 1). HDL, on the other hand, decreases the accumulation of lipid peroxides on LDL over several hours.²⁹ Furthermore, the effect of the incorporation of fat-soluble antioxidants, such as vitamin E, into lipoproteins may be to increase cholesteryl ester transfer protein activity,³⁹ which is increasingly regarded as potentially atherogenic.²³ This would counteract the theoretically favorable, although limited, protection of LDL against oxidation by fat-soluble antioxidants. In any case, when these are oxidized, they themselves become pro-oxidant in the process, unless they can hand on the electrons they acquire during oxidation to another reducing agent, such as ascorbate or urate, which may not be possible in the atherosclerotic plaque.

View this table: [in this window] [in a new window]   Table 1. Effect of Antioxidant Supplementation in Healthy Volunteers on Early Lag Phase in Conjugated Diene Formation and Later Accumulation of Lipid Peroxides on LDL When Incubated With Cu2+ in Presence and Absence of HDL

	PON1 and Other Enzymatic Activities of HDL

Top Abstract Introduction Antioxidant Role of HDL PON1 and Other Enzymatic... Sources of Variation in... PON1 and Atherosclerosis Potential for Modifying Serum... Other Diseases Associated With... Conclusion References

 
Of the proteins present on HDL that possess enzymatic (usually hydrolytic) activity (Table 2), we advanced the hypothesis that PON1 in the human was principally responsible for the breakdown of lipid peroxides before they could accumulate on LDL.^{28 29 40} This hypothesis was originally based on our finding that purified PON1 was highly effective in preventing lipid peroxidation of LDL,^{28 40} which has since been confirmed.^{31 41 42 43 44 45} In our experiments, PON1 was substantially more effective than was LCAT or apoA-I in protecting LDL against oxidation, although the combination of all 3 did slightly enhance the effect of PON1 alone⁴² (Figure 2). Platelet-activating factor (PAF) acetyl hydrolase (PAFAH) has an action resembling that postulated for PON1. However, PON1, like PAFAH, can also release acetate from the Sn2 position of PAF by hydrolysis.⁴⁶ Although PAFAH is undoubtedly present in LDL, in our view it is not established that the PAFAH activity of HDL is due to anything other than PON1.⁴⁶ Avian HDL has no PON1 activity and fails to protect human LDL against lipid peroxidation.⁴³ Experiments with PON1 knockout mice were also unequivocal: serum PAFAH activity was unaltered in the PON1 knockout mice, yet their HDL failed to protect LDL against oxidation.⁴⁴ They were susceptible to diet-induced atherosclerosis.⁴⁴ Experiments with inhibitors of PON1 also suggest that it is responsible for the antioxidant effect of HDL.⁴¹ However, one piece of evidence that has sometimes been interpreted as implying that PON1 is not the major source of the antioxidant activity of HDL is that the effect does not appear to be calcium dependent.³³ The hydrolytic activity of PON1 against organophosphate substrates is highly calcium dependent. However, it has recently been shown with purified PON1 that calcium is not required for it to prevent the accumulation of lipid peroxides⁴¹ (Table 3). Furthermore, the cysteine group at amino acid position 283 is essential for the protection of LDL against oxidation but not for organophosphate hydrolysis.⁴¹ This suggests either that conformational changes in the active site of PON1 (which render it unable to catalyze organophosphate hydrolysis) can occur while it retains its antioxidant activity or that it possesses 2 active sites: the antioxidant site, dependent on Cys283, and the other site (organophosphate hydrolysis), dependent on calcium. In either case, it cannot be assumed that retention of the capacity to hydrolyze substrates, such as paraoxon, phenylacetate, or diazoxon, necessarily reflects the presence or absence of significant PON1 antioxidant capacity.

View this table: [in this window] [in a new window]   Table 2. Proteins Present in Human HDL That Possess Enzymatic Activity

View larger version (20K): [in this window] [in a new window]   Figure 2. Lipid peroxide accumulation on LDL incubated under oxidizing conditions alone and in the presence of apoA-I (AI), LCAT, PON1, and combinations of these.42

View this table: [in this window] [in a new window]   Table 3. Four Different Activities of PON and Influence of Calcium Ions, Cysteine at Position 283 in Amino Acid Sequence of PON, and 192 QR Polymorphism

PON1 is located in a subfraction of HDL that contains apoA-I and clusterin (apoJ).^{47 48 49} We have suggested that this subfraction of HDL may function to protect cell membranes generally against lipid peroxidation and other toxic effects.³⁴ Clusterin has likewise been proposed as a protein protecting cell membranes.⁵⁰ HDL is the most abundant protein in the tissue fluid and, indeed, the only lipoprotein in the central nervous system. That PON1 is present in the tissue fluid can be inferred from its presence in blister fluid.⁵¹ It is unlikely that its antioxidant function has evolved to protect humans against atheroma, a disease that appears to have been prevalent for less than a century.⁵² Therefore, its antioxidant capacity is probably part of a much older protective role, and LDL shares in this protection because of its resemblance to a cell membrane. Although PON1 was discovered as the result of its ability to hydrolyze xenobiotic toxins, there are natural organophosphate toxins⁵³ and numerous other exogenous and endogenous esters, such as homocysteine thiolactone,⁵⁴ other lactones, and cyclic carbonates,^{55 56} which it can detoxify by catalyzing their hydrolysis.⁵³

	Sources of Variation in PON1 Activity

Top Abstract Introduction Antioxidant Role of HDL PON1 and Other Enzymatic... Sources of Variation in... PON1 and Atherosclerosis Potential for Modifying Serum... Other Diseases Associated With... Conclusion References

 
Serum PON1 activity and concentration are correlated with the HDL cholesterol and apoA-I concentration in most healthy populations studied, but the relationship is not a strong one,⁵⁷ which is compatible with the PON1-containing HDL being a subspecies, the concentration of which can vary considerably independently of the major part of HDL. In extreme examples of HDL deficiency, such as Tangier disease and fish eye disease, serum PON1 is profoundly diminished,^{58 59} but in other HDL deficiencies, this is not always the case.⁶⁰ This may be relevant to why some HDL deficiency states are associated with premature coronary heart disease (CHD), but others are not. What is certain, however, is that there are major influences on serum PON1 activity that are concentration independent of those governing HDL as a whole. PON1 has 2 amino acid polymorphisms, one at position 55 (methionine/leucine, M/L) and the other at position 192 (arginine/glutamine, R/Q).⁶¹ Paraoxon hydrolytic activity is greatest with HDL and with purified PON1 from PON1 192 RR and PON1 55 LL individuals and least with PON1 192 QQ and PON1 55 MM individuals.^{45 61 62} Heterozygotes have intermediate levels of activity. A similar pattern of substrate specificity is observed with some other oxons, such as methyl paraoxon and chlorthion-oxon, and with armine.⁶² On the other hand, the capacity of paraoxonase alloenzymes to protect LDL from oxidation is the complete reverse of that of paraoxon hydrolytic activity. Thus, PON1 55 MM/PON1 192 QQ individuals have HDL and PON1 associated with the greatest protective capacity.^{41 63 64} These alloenzymes are also most active in hydrolyzing diazoxon and the nerve gases sarin and soman.⁶² There is yet another group of substrates, such as phenyl acetate, chlorpyrifos oxon, and 2-naphthyl acetate, against which all the alloenzymes of PON1 have a similar hydrolytic activity.⁶²

Healthy populations in different countries also have different serum PON1 activity, which varies not simply with genotype distribution in those countries but also independently of genotype.² Nutritional differences may well be the explanation, but thus far, there is little experimental evidence for this. In wild-type rabbits and transgenic rabbits expressing human apoA-I, changing from standard laboratory chow to a cholesterol-rich diet markedly decreases serum PON1 activity.¹² Degraded cooking oil has been reported to lower serum PON1 in humans,⁶⁵ and alcohol has been reported to raise it.⁶⁶ We also have preliminary data to suggest that Gulf War veterans have low serum PON1 activity that is not explained by genotype distribution, perhaps because exposure to chemicals (possibly organophosphates themselves) may cause a long-term decrease in serum PON1 activity.^{67 68}

Some experimental evidence suggests that a decrease in serum PON1 activity may occur as part of an inflammatory response.^{69 70 71} It is interesting to speculate that not only might a chronic decrease in PON1 activity increase susceptibility to atherosclerosis but that more acute declines due to some intercurrent acute inflammatory condition could exacerbate LDL oxidation and, thus, foam cell generation in a critical part of a preexisting atheromatous lesion, which may weaken its fibrous cap, predisposing it to rupture and to an acute ischemic event due to clotting on the torn surface of the lesion.

	PON1 and Atherosclerosis

Top Abstract Introduction Antioxidant Role of HDL PON1 and Other Enzymatic... Sources of Variation in... PON1 and Atherosclerosis Potential for Modifying Serum... Other Diseases Associated With... Conclusion References

 
Numerous studies have been conducted to determine whether people with the PON1 192 R alloenzyme are more prone to CHD than are those with the Q alloenzyme. These have all reported that either this is the case or that there was no association with either of the PON1 192 alleles.^{72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88} We have recently conducted a meta-analysis (Figure 3) that reveals a statistically significant overall association between the PON1 192 R allele and the presence of CHD if the Q alloenzyme of PON1 is more protective against CHD than is the R alloenzyme, as expected. There are also reports that the PON1 R allele increases the likelihood of CHD occurring by increasing susceptibility to other established risk factors, such as diabetes mellitus,⁷² cigarette smoking,⁸⁹ and age.⁹⁰ Some other studies have also shown an association between the PON1 55 L allele and atherosclerosis,^{91 92 93 94} although others have not.^{95 96} It should be noted that all these studies have been case-control studies and that, as yet, there are no prospective investigations. However, most criticism should be reserved for claims that an association between CHD and PON1 genotype would be a valid test of the hypothesis that PON1 protects against CHD. This is because there is substantial interindividual variation in PON1 activity, which is independent of the 55 or 192 polymorphisms. Thus, there are many individuals whose serum PON1 activity is low with respect to all substrates. This may be due to acquired factors acting on the composition of the lipid environment of HDL, in which PON1 operates, or on the promoter region of the PON1 gene,⁹⁷ or in some manner as yet unidentified. When PON1 activity is measured directly in patients with CHD, it is approximately half that of disease-free control subjects^{98 99 100} (also B. Mackness, unpublished data, 2001). This appears to be the case even within a few hours of the onset of cardiac ischemic chest pain in survivors of myocardial infarction, suggesting that low serum PON1 activity may have preceded the event.⁹⁹ Low serum PON1 activity independent of genotype has been reported with diseases, which are known to be associated with CHD, such as diabetes mellitus,^{7 101 102 103 104} hypercholesterolemia,¹⁰¹ and renal failure.^{88 105 106 107} In the case of diabetes, the serum PON1 activity is decreased even before the onset of clinical CHD⁷ and in animal models of diabetes.¹⁰⁸

View larger version (19K): [in this window] [in a new window]   Figure 3. Results of a meta-analysis of case-control studies reporting on the odds ratio of the likelihood of cases of CHD having a PON1 192 R allele relative to controls. Confidence intervals that cross unity are not statistically significant. Overall, the odds are significantly increased (open diamond). References are as follows: Antikainen et al,80 Aubó et al,81 Cascorbi et al,82 Hasselwander et al,88 Herrmann et al,83 Mackness et al,100 Ombres et al,84 Pati and Pati,77 Pfohl et al,76 Rice et al,85 Ruiz et al,72 Sanghera et al,79 Serrato and Marian,73 Imai et al,78 Odawara et al,74 Suehiro et al,86 Ko et al,87 and Zama et al.75

We have shown that PON1 immunoreactivity is increasingly present in the arterial wall as atheroma advances.¹⁰⁹ At present, there is no way of knowing whether this is part of a protective response, but a recent study has shown that PON1 has the ability ex vivo to hydrolyze lipid peroxides within human carotid and coronary atheromatous lesions.¹¹⁰

	Potential for Modifying Serum PON1 Activity

Top Abstract Introduction Antioxidant Role of HDL PON1 and Other Enzymatic... Sources of Variation in... PON1 and Atherosclerosis Potential for Modifying Serum... Other Diseases Associated With... Conclusion References

 
As was previously discussed, nutritional effects on serum PON1 activity may prove rewarding to study. There is also considerable interest in the potential pharmacological effects on PON1 activity. Of the lipid-lowering drugs, fibric acid derivatives have been reported to raise serum PON1 activity in 2 studies,^{111 112} but this effect was not found in 2 other studies.^{113 114} Statin therapy may raise PON1 activity.¹¹⁵ In mice, polyphenols have been reported to increase serum PON1 activity,¹¹⁶ but this interesting group of compounds has not, so far, been studied in humans in this context.

	Other Diseases Associated With Low Serum PON1 Activity

Top Abstract Introduction Antioxidant Role of HDL PON1 and Other Enzymatic... Sources of Variation in... PON1 and Atherosclerosis Potential for Modifying Serum... Other Diseases Associated With... Conclusion References

 
Susceptibility to organophosphate toxicity is highly likely to be related to PON1 activity and genotype.¹¹⁷ Most organophosphates are neurotoxins. Their acute effects in blocking neuromuscular transmission are well known, but chronic low-level exposure can produce neuropathy and perhaps neuropsychiatric effects.¹¹⁸ Sheep-dip workers and other industrial groups exposed to organophosphates are being studied in this regard to establish whether those with lower serum PON1 activity are more susceptible. There also remains the possibility that low serum PON1 activity predisposes one to other neurological disorders, perhaps because of the susceptibility to exposure to neurotoxins that is encountered in the course of everyday life (and certainly organophosphates are widely encountered in the diet and household) or because lipid peroxidation is a factor in the pathogenesis of disorders other than atherogenesis. Thus, low serum PON1 activity is encountered in diabetic neuropathy (and other microvascular disease) even in the absence of clinically evident CHD,⁷ and the PON1 gene is linked with diabetic retinopathy.¹¹⁹ There are conflicting reports of an association between PON1 and Parkinson’s disease.^{120 121}

	Conclusion

Top Abstract Introduction Antioxidant Role of HDL PON1 and Other Enzymatic... Sources of Variation in... PON1 and Atherosclerosis Potential for Modifying Serum... Other Diseases Associated With... Conclusion References

 
PON1 would thus seem worthy of further study as an etiologic factor in the development of CHD and perhaps other diseases. Additional information is required particularly about nutritional and pharmacological effects on serum PON1 activity that might lead to intervention trials to test its capacity to prevent atheroma. Information from prospective cohort studies may also be valuable, as would a more detailed knowledge of the basic biochemistry of PON1 action and its interrelations with other HDL enzymes.

	Acknowledgments

 
This work received support from the British Heart Foundation, Medical Research Council, and National Health Service Research and Development Levy. We are grateful to C. Price for expertly preparing this manuscript and to Drs C. Roberts and E. Hill of the Biostatistics Unit of the University of Manchester School of Epidemiology and Public Health for performing the meta-analysis.

	Footnotes

 
Previously presented in part as a lecture given by Prof P.N. Durrington at the European Atherosclerosis Society workshop on Low HDL and Cardiovascular Disease, Istanbul, Turkey, April 7–9, 2000.

Received October 19, 2000; accepted February 8, 2001.

	References

Top Abstract Introduction Antioxidant Role of HDL PON1 and Other Enzymatic... Sources of Variation in... PON1 and Atherosclerosis Potential for Modifying Serum... Other Diseases Associated With... Conclusion References

 
1. Primo-Parma SL, Sorenson RC, Teiber J, La Du BN. The human serum paraoxonase/arylesterase gene (PON1) is one member of a multigene family. Genomics. 1996;33:498–509.[Medline] [Order article via Infotrieve]

2. Mackness MI, Mackness B, Durrington PN, Connelly PW, Hegele RA. Paraoxonase: biochemistry, genetics and relationship to plasma lipoproteins. Curr Opin Lipidol. 1996;7:69–76.[Medline] [Order article via Infotrieve]

3. Hegele RA. Paraoxonase genes and disease. Ann Med. 1999;31:217–224.[Medline] [Order article via Infotrieve]

4. Clendenning JB, Humbert R, Green ED, Wood C, Traver D, Furlong CE. Structural organisation of the human PON1 gene. Genomics. 1996;35:586–589.[Medline] [Order article via Infotrieve]

5. Rowles J, Scherer SW, Xi T, Majer M, Nickle DC, Rommans JM, Popov KM, Harris RA, Riebow NL, Xia J, et al. Cloning and characterisation of PDK4 on 7q21.3 encoding a fourth pyruvate dehydrogenase kinase isoenzyme in human. J Biol Chem. 1996;271:22376–22382.[Abstract/Free Full Text]

6. Hegele RA, Connelly PW, Scherer SW, Hanley AJG, Harris SB, Tsui L-C, Zinman B. Paraoxonase-2 gene (PON2) G148 variant associated with elevated fasting plasma glucose in non-insulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1997;82:3373–3377.[Abstract/Free Full Text]

7. Mackness B, Durrington PN, Abuashia B, Boulton AJM, Mackness MI. Low paraoxonase activity in type II diabetes complicated by retinopathy. Clin Sci. 2000;98:355–363.[Medline] [Order article via Infotrieve]

8. Draganov DI, Stetson PL, Watson CE, Billecke SS, La Du BN. Rabbit serum paraoxonase 3 (PON3) is a high density lipoprotein-associated lactonase and protects low density lipoprotein against oxidation. J Biol Chem. 2000;275:33435–33442.[Abstract/Free Full Text]

9. Spady DK. Reverse cholesterol transport and atherosclerosis. Circulation. 1999;100:576–578.[Free Full Text]

10. Badimon JJ, Badimon L, Fuster V. Regression of atherosclerotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit. J Clin Invest. 1990;85:1234–1241.

11. Duverger N, Kruth H, Emmanuel F, Caillaud JM, Viglietta C, Castro G, Tailleux A, Fievet C, Fruchart JC, Houdebine LM, et al. Inhibition of atherosclerosis development in cholesterol-fed human apolipoprotein A-I-transgenic rabbits. Circulation. 1996;94:713–717.[Abstract/Free Full Text]

12. Mackness MI, Bouiller A, Hennuyer M, Mackness B, Hall M, Tailleux A, Duriez P, Delfly B, Durrington PN, Fruchart, J-C, et al. Paraoxonase activity is reduced by a pro-atherosclerotic diet in rabbits. Biochem Biophys Res Commun. 2000;269:232–236.[Medline] [Order article via Infotrieve]

13. Li H, Reddick RL, Maeda N. Lack of apo A-1 is not associated with increased susceptibility to atherosclerosis in mice. Arterioscler Thromb. 1993;13:1814–1821.[Abstract/Free Full Text]

14. Brooks-Wilson A, Marcil M, Clee SM, Zang LH, Roomp K, van Dam M, Yu L, Brewer C, Collins JA, Molhuizen HO, et al. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet. 1999;22:336–345.[Medline] [Order article via Infotrieve]

15. Bodzioch M, Orso E, Klucken J, Langmann T, Bottcher A, Diederich W, Drobnik W, Barlage S, Buchler C, Porsch-Ozcurumez M, et al. The gene encoding ATP-binding cassette transport 1 is mutated in Tangier disease. Nat Genet. 1999;22:347–351.[Medline] [Order article via Infotrieve]

16. Rust S, Rosier M, Funke H, Real J, Amoura Z, Piette JC, Deleuze JF, Brewer HB, Duverger N, Denefle P, et al. Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet. 1999;22:352–355.[Medline] [Order article via Infotrieve]

17. Remaley AT, Rust S, Rosier M, Knapper C, Naudin L, Broccardo C, Peterson KM, Koch C, Arnould I, Prades C, et al. Human ATP-binding cassette transporter 1 (ABC1): genomic organization and identification of the genetic defect in the original Tangier disease kindred. Proc Natl Acad Sci U S A. 1999;96:12685–12690.[Abstract/Free Full Text]

18. Lawn RM, Wade DP, Garvin MR, Wang X, Schwartz K, Porter G, Seilhamer JJ, Vaughan AM, Oram JF. The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway. J Clin Invest. 1999;104:R25–R31.

19. Chait A, Brazg R, Tribble D, Krauss R. Susceptibility of small, dense, low-density lipoproteins to oxidative modification in subjects with the atherogenic lipoprotein phenotype, pattern B. Am J Med. 1993;94:350–356.[Medline] [Order article via Infotrieve]

20. Griffin BA, Freeman DJ, Tait G, Thomson J, Caslake MJ, Packard CJ, Shepherd J. Role of plasma triglyceride in the regulation of plasma low density lipoprotein (LDL) subfractions: relative contribution of small, dense LDL to coronary heart disease risk. Atherosclerosis. 1994;106:241–253.[Medline] [Order article via Infotrieve]

21. Bhatnagar D, Durrington PN, Mackness MI, Arrol S, Winocour PH, Prais H. Effects of treatment of hypertriglyceridaemia with gemfibrozil on serum lipoproteins and the transfer of cholesteryl ester from high density lipoproteins to low density lipoproteins. Atherosclerosis. 1992;92:49–57.[Medline] [Order article via Infotrieve]

22. Grundy SM, Vega GL, Otvos JD, Rainwater DL, Cohen JC. Hepatic lipase activity influences high density lipoprotein subclass distribution in normotriglyceridaemic men: genetic and pharmacological evidence. J Lipid Res. 1999;40:229–234.[Abstract/Free Full Text]

23. Okamoto H, Yonemori F, Wakitani K, Minowa T, Maeda K, Shinkai H. A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits. Nature. 2000;406:203–207.[Medline] [Order article via Infotrieve]

24. Inazu A, Koizumi J, Mabuchi H. Cholesteryl ester transfer protein and atherosclerosis. Curr Opin Lipidol. 2000;11:389–396.[Medline] [Order article via Infotrieve]

25. Witztum JL, Steinberg D. Role of oxidized low density lipoprotein in atherogenesis. J Clin Invest. 1991;88:1785–1792.

26. Hessler JR, Robertson AL, Chisolm GM. LDL-induced cytotoxicity and its inhibition by HDL in human vascular smooth muscle and endothelial cells in culture. Atherosclerosis. 1979;32:213–229.[Medline] [Order article via Infotrieve]

27. Parthasarathy S, Barnett J, Fong LG. High-density lipoprotein inhibits the oxidative modification of low-density lipoprotein. Biochim Biophys Acta. 1990;1044:275–283.[Medline] [Order article via Infotrieve]

28. Mackness MI, Arrol S, Durrington PN. Paraoxonase prevents accumulation of lipoperoxides in low-density lipoprotein. FEBS Lett. 1991;286:152–154.[Medline] [Order article via Infotrieve]

29. Mackness MI, Abbott CA, Arrol S, Durrington PN. The role of high density lipoprotein and lipid-soluble antioxidant vitamins in inhibiting low-density lipoprotein oxidation. Biochem J. 1993;294:829–835.

30. Navab M, Imes SS, Hama SY, Hough GP, Ross LA, Bork RW, Valente AJ, Berliner JA, Drinkwater DC, Laks H, et al. Monocyte transmigration induced by modification of low density lipoprotein in cocultures of human aortic wall cells is due to induction of monocyte chemotactic protein 1 synthesis and is abolished by high density lipoprotein. J Clin Invest. 1991;88:2039–2046.

31. Watson AD, Berliner JA, Hama SY, La Du BN, Fault KF, Fogelman AM, Navab M. Protective effect of high density lipoprotein associated paraoxonase: inhibition of the biological activity of minimally oxidised low-density lipoprotein. J Clin Invest. 1995;96:2882–2891.

32. Aviram M, Rosenblat M, Bisgaier CL, Newton RS, Primo-Parmo SL, La Du BN. Paraoxonase inhibits high-density lipoprotein and preserves its functions. J Clin Invest. 1998;101:1581–1590.[Medline] [Order article via Infotrieve]

33. Graham A, Hassall DG, Rafique S, Owen JS. Evidence for a paraoxonase independent inhibition of low-density lipoprotein oxidation by high-density lipoprotein. Atherosclerosis. 1997;135:193–204.[Medline] [Order article via Infotrieve]

34. Mackness MI, Durrington PN. High density lipoprotein, its enzymes and its potential to influence lipid peroxidation. Atherosclerosis. 1995;115:243–253.[Medline] [Order article via Infotrieve]

35. Steinbrecher UP, Lougheed M, Kwan W-C, Dirks M. Recognition of oxidised low density lipoprotein by the scavenger receptor of macrophages results from derivatisation of apolipoprotein B by products of fatty acid peroxidation. J Biol Chem. 1989;264:15216–15223.[Abstract/Free Full Text]

36. Mackness MI, Sangvanich P, Mackness B, Durrington PN, Gaskill S. HDL prevents the formation of aldehyde adducts of apolipoprotein B during the oxidation of LDL. Atherosclerosis. 2000;151:260.

37. Myant NB. The Biology of Cholesterol, and Related Steroids. London, UK: William Heinemann Medical Books Ltd; 1981.

38. The Heart Outcomes Prevention Evaluation Study Investigators. Vitamin E supplementation and cardiovascular events in high-risk patients. N Engl J Med. 2000;342:154–160.[Abstract/Free Full Text]

39. Arrol S, Mackness MI, Durrington PN. Vitamin E supplementation increases the resistance of both LDL and HDL to oxidation and increases cholesteryl ester transfer activity. Atherosclerosis. 2000;150:129–134.[Medline] [Order article via Infotrieve]

40. Mackness MI, Arrol S, Abbott CA, Durrington PN. Protection of low-density lipoprotein against oxidative modification by high-density lipoprotein associated paraoxonase. Atherosclerosis. 1993;104:129–135.[Medline] [Order article via Infotrieve]

41. Aviram M, Billecke S, Sorenson R, Bisgaier C, Newton R, Rosenblat M, Erogul J, Hsu C, Dunlop C, La Du BN. Paraoxonase active site required for protection against LDL oxidation involves its free sulfhydryl group and is different from that required for its arylesterase/paraoxonase activities: selective active of human paraoxonase alloenzymes Q and R. Arterioscler Thromb Vasc Biol. 1998;10:1617–1624.

42. Arrol S, Mackness MI, Durrington PN. High-density lipoprotein associated enzymes and the prevention of low-density lipoprotein oxidation. Eur J Lab Med. 1996;4:33–38.

43. Mackness B, Durrington PN, Mackness MI. Lack of protection against oxidative modification of LDL by avian HDL. Biochem Biophys Res Commun. 1998;247:443–446.[Medline] [Order article via Infotrieve]

44. Shih DM, Gu L, Xia Y-R, Navab M, Li W-F, Hama S, Castellani LW, Furlong CE, Costa LG, Fogelman AM, et al. Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis. Nature. 1998;394:284–287.[Medline] [Order article via Infotrieve]

45. Mackness B, Mackness MI, Arrol S, Turkie W, Durrington PN. Effect of the molecular polymorphisms of human paraoxonase (PON1) on the rate of hydrolysis of paraoxon. Br J Pharmacol. 1997;112:265–268.

46. Rodrigo L, Mackness B, Durrington PN, Hernandez A, Mackness MI. Hydrolysis of platelet-activating factor by human serum paraoxonase. Biochem J. 2001;354:1–7.[Medline] [Order article via Infotrieve]

47. Mackness MI, Walker CH. "A"-esterase activity in the lipoprotein fraction of sheep serum. Biochem Pharmacol. 1981;30:903–906.[Medline] [Order article via Infotrieve]

48. Kelso GJ, Stuart WD, Richter RJ, Furlong CE, Jordan-Starck TC, Harmony JAK. Apolipoprotein J is associated with paraoxonase in human plasma. Biochemistry. 1994;33:832–839.[Medline] [Order article via Infotrieve]

49. Blatter M-C, James RW, Messmer S, Barja F, Pometta D. Identification of a distinct human high-density lipoprotein subspecies defined by a lipoprotein-associated protein, K-85: identity of K-85 with paraoxonase. Eur J Biochem. 1993;211:871–879.[Medline] [Order article via Infotrieve]

50. Jordan-Starck TC, Witte DP, Aronow BJ, Harmony JAK. Apolipoprotein J: a membrane policeman? Curr Opin Lipidol. 1992;3:75–85.

51. Mackness MI, Mackness B, Arrol S, Wood G, Bhatnagar D, Durrington PN. Presence of paraoxonase in human interstitial fluid. FEBS Lett. 1997;416:377–380.[Medline] [Order article via Infotrieve]

52. Herrick JB. Certain clinical features of sudden obstruction of the coronary arteries. JAMA. 1912;59:2015–2020.

53. La Du BN. Structural and functional diversity of paraoxonases. Nat Med. 1996;2:1186–1187.[Medline] [Order article via Infotrieve]

54. Jakubowski H. Calcium-dependent human serum homocysteine thiolactone hydrolase. J Biol Chem. 2000;275:3957–3962.[Abstract/Free Full Text]

55. Biggadike K, Angell RM, Burgess CM, Farrell RM, Hancock AP, Harker AJ, Irving WR, Ioannou C, Procopiou PA, Shaw RE, et al. Selective plasma hydrolysis of glucocorticoid -lactones and cyclic carbonates by the enzyme paraoxonase. J Med Chem. 2000;43:19–21.[Medline] [Order article via Infotrieve]

56. Billecke S, Draganov D, Counsell R, Stetson P, Watson C, Hsu C, La Du BN. Human serum paraoxonase (PON1) isoenzymes Q and R hydrolyse lactones and cyclic carbonate esters. Drug Metab Dispos. 2000;28:1335–1342.[Abstract/Free Full Text]

57. Mackness B, Mackness MI, Durrington PN, Arrol S, Evans AE, McMaster D, Ferrières J, Ruidavets J-B, Williams NR, Howard AN. Paraoxonase activity in two healthy populations with differing rates of coronary heart disease. Eur J Clin Invest. 2000;30:4–10.[Medline] [Order article via Infotrieve]

58. Mackness MI, Walker CH, Carlson LA. Low A-esterase activity in serum of patients with fish-eye disease. Clin Chem. 1987;33:587–588.[Abstract/Free Full Text]

59. Mackness MI, Peuchant E, Dumon M-F, Walker CH, Clerc M. Absence of A-esterase activity in the serum of a patient with Tangier disease. Clin Biochem. 1989;22:475–478.[Medline] [Order article via Infotrieve]

60. James RW, Blatter Garin MC, Calabresi L, Miccoli R, von Eckardstein A, Tilly-Kiesi M, Taskinen MR, Assmann G, Franceschini G. Modulated serum activities and concentrations of paraoxonase in high density lipoprotein deficiency states. Atherosclerosis. 1998;139:77–82.[Medline] [Order article via Infotrieve]

61. Adkins S, Gan KN, Mody M, La Du BN. Molecular basis for the polymorphic forms of human serum paraoxonase/arylesterase: glutamine or arginine at position 191, for the respective A or B allozymes. Am J Hum Genet. 1993;52:598–608.[Medline] [Order article via Infotrieve]

62. Davies HG, Richter RJ, Keifer M, Broomfield CA, Sowalla J, Furlong CE. The effect of the human serum paraoxonase polymorphism is reversed with diazoxon, soman and sarin. Nat Genet. 1996;14:334–336.[Medline] [Order article via Infotrieve]

63. Mackness MI, Arrol S, Mackness B, Durrington PN. The alloenzymes of paraoxonase determine the effectiveness of high-density lipoprotein in protecting low density lipoprotein against lipid-peroxidation. Lancet. 1997;349:851–852.[Medline] [Order article via Infotrieve]

64. Mackness B, Mackness MI, Arrol S, Turkie W, Durrington PN. Effect of the human serum paraoxonase 55 and 192 genetic polymorphisms on the protection by high density lipoprotein against low density lipoprotein oxidative modification. FEBS Lett. 1998;423:57–60.[Medline] [Order article via Infotrieve]

65. Sutherland WHF, Walker RJ, de Jong SA, van Rij AM, Phillips V, Walker HL. Reduced postprandial serum paraoxonase activity after a meal rich in used cooking fat. Arterioscler Thromb Vasc Biol. 1999;19:1340–1347.[Abstract/Free Full Text]

66. van der Gaag MS, van Tol A, Scheek LM, James RW, Urgert R, Schaafsma G, Hendriks HF. Daily moderate alcohol consumption increases serum paraoxonase activity: a diet-controlled, randomised intervention study in middle-aged men. Atherosclerosis. 1999;147:405–410.[Medline] [Order article via Infotrieve]

67. Mackness B, Durrington PN, Mackness MI. Low paraoxonase in Persian Gulf War veterans self-reporting Gulf War syndrome. Biochem Biophys Res Commun. 2000;276:729–733.[Medline] [Order article via Infotrieve]

68. Haley RW, Billecke S, La Du BN. Association of low PON1 type Q (type A) arylesterase activity with neurologic symptom complexes in Gulf War veterans. Toxicol Appl Pharmacol. 1999;157:227–233.[Medline] [Order article via Infotrieve]

69. Van Lenten BJ, Hama SY, de Beer FC, Stafforini DM, McIntyre TM, Prescott SM, La Du BN, Fogelman AM, Navab M. Anti-inflammatory HDL becomes pro-inflammatory during the acute phase response. J Clin Invest. 1995;96:2758–2767.

70. Feingold KR, Memon RA, Moser AH, Grunfeld C. Paraoxonase activity in the serum and hepatic mRNA levels decrease during the acute phase response. Atherosclerosis. 1998;139:307–315.[Medline] [Order article via Infotrieve]

71. Hedrick CC, Hassan K, Hough GP, Yoo J, Simzar S, Quinto CR. Short-term feeding of atherogenic diet to mice results in reduction of HDL and paraoxonase that may be mediated by an immune mechanism. Arterioscler Thromb Vasc Biol. 2000;20:1946–1952.[Abstract/Free Full Text]

72. Ruiz J, Blanche H, James RW, Garin M-CB, Vaisse C, Charpentier G, Cohen N, Morabia A, Passa P, Froguel P. Gln-Arg192 polymorphism of paraoxonase and coronary heart disease in type 2 diabetes. Lancet. 1995;346:869–872.[Medline] [Order article via Infotrieve]

73. Serrato M, Marian AJ. A variant of human paraoxonase/arylesterase (HUMPONA) gene is a risk factor for coronary artery disease. J Clin Invest. 1995;96:3005–3008.

74. Odawara M, Tachi Y, Yamashita K. Paraoxonase polymorphism (Gln¹⁹²-Arg) is associated with coronary heart disease in Japanese non-insulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1997;82:2257–2260.[Abstract/Free Full Text]

75. Zama T, Murata M, Matsubara Y, Kawano K, Aoki N, Yoshino H, Watanabe G, Ishikawa K, Ikeda Y. A 192-Arg variant of the human paraoxonase (HUMPONA) gene polymorphism is associated with an increased risk for coronary artery disease in the Japanese. Arterioscler Thromb Vasc Biol. 1997;17:3565–3569.[Abstract/Free Full Text]

76. Pfohl M, Koch M, Euderle MD, Kühn R, Füllhase J, Karsch KR, Haring HU. Paraoxonase 192 Glu/Arg gene polymorphism, coronary artery disease, and myocardial infarction in type 2 diabetes. Diabetes. 1999;192:48:623–627.

77. Pati N, Pati U. Paraoxonase gene polymorphism and coronary artery disease in Indian subjects. Int J Cardiol. 1998;66:165–168.[Medline] [Order article via Infotrieve]

78. Imai Y, Marita H, Kurihara H, Sugiyama T, Kato N, Ebihara A, Hamada C, Kurihara Y, Shindo T, Oh-hashi Y, et al. Evidence for association between paraoxonase gene polymorphisms and atherosclerotic diseases. Atherosclerosis. 2000;149:435–442.[Medline] [Order article via Infotrieve]

79. Sanghera DK, Saha N, Aston CE, Kamboh MI. Genetic polymorphism of paraoxonase and the risk of coronary heart disease. Arterioscler Thromb Vasc Biol. 1997;17:1067–1073.[Abstract/Free Full Text]

80. Antikainen M, Murtomäki S, Syvänne M, Pahlman R, Tahvanainen E, Jauhiainen M, Frick MH, Ehnholm C. The Gln-Arg polymorphism of human paraoxonase gene (HUMPONA) is not associated with the risk of coronary artery disease in Finns. J Clin Invest. 1996;191:98:883–885.

81. Aubó C, Sentí M, Marragut J, Tomá M, Vila J, Sala J, Masiá R. Risk of myocardial infarction with Gln/Arg 192 polymorphisms in the human paraoxonase gene and diabetes mellitus. Eur Heart J. 2000;21:31–38.

82. Cascorbi I, Laule M, Mrozikiewicz PM, Mrozikiewicz A, Andel C, Baumann G, Roots I, Stangl K. Mutations in the human paraoxonase 1 gene: frequencies, allelic linkages and association with coronary artery disease. Pharmacogenetics. 1999;9:755–761.[Medline] [Order article via Infotrieve]

83. Herrmann SM, Blanc H, Poirier O, Arveiter D, Luc G, Evans A, Marques-Vidal P, Bard JM, Cambien F. The Gln/Arg polymorphism of human paraoxonase (PON 192) is not related to myocardial infarction in the ECTIM study. Atherosclerosis. 1996;126:299–304.[Medline] [Order article via Infotrieve]

84. Ombres D, Pannitteri G, Moutali A, Candeloro A, Seccareccia F, Campagna F, Cantini R, Campa PP, Ricci G, Arca M. The Gln-Arg 192 polymorphism of the human paraoxonase gene is not associated with coronary artery disease in Italian patients. Arterioscler Thromb Vasc Biol. 1998;18:1611–1616.[Abstract/Free Full Text]

85. Rice GI, Ossei-Geoning N, Stickland MH, Grant PJ. The paraoxonase Gln-Arg polymorphism in subjects with ischaemic heart disease. Coron Artery Dis. 1997;192:8:677–682.

86. Suehiro T, Nakauchi Y, Yamamoto M, Arii K, Itoh H, Hamashige N, Hashimoto K. Paraoxonase gene polymorphism in Japanese subjects with coronary heart disease. Int J Cardiol. 1996;57:69–73.[Medline] [Order article via Infotrieve]

87. Ko Y-L, Ko Y-S, Wang S-M, Hsu L-A, Chang C-J, Chu P-H, Cheng NJ, Chen WJ, Chiang CW, Lee YS. The Gln-Arg 191 polymorphism of the human paraoxonase gene is not associated with the risk of coronary artery disease among Chinese in Taiwan. Atherosclerosis. 1998;141:259–264.[Medline] [Order article via Infotrieve]

88. Hasselwander O, Savage DA, McMaster D, Loughrey CM, McNamee PT, Middleton D, Nicholls DP, Maxwell AP, Young IS. Paraoxonase polymorphisms are not associated with cardiovascular risk in renal transplant recipients. Kidney Int. 1999;56:289–298.[Medline] [Order article via Infotrieve]

89. Senti M, Aubo C, Tomas M. Differential effects of smoking on myocardial infraction risk according to the Gln/Arg 192 variants of the human paraoxonase gene. Metabolism. 2000;49:557–559.[Medline] [Order article via Infotrieve]

90. Senti M, Tomas M, Vila J, Marrugat J, Elosua R, Sala J, Masia R. Relationship of age-related myocardial infarction risk and Gln/Arg 192 variants of the human paraoxonase gene: the Regicor study. Atherosclerosis. In press.

91. Sanghera DK, Aston CE, Saha N, Kamboh MI. DNA polymorphisms in two paraoxonase genes (PON1 and PON2) are associated with the risk of coronary heart disease. Am J Hum Genet. 1998;62:36–44.[Medline] [Order article via Infotrieve]

92. Salonen JT, Malin R, Toumaineu T-P, Nyyssönen K, Lakka TA, Lehtimäki T. Polymorphism in high density lipoprotein gene and risk of acute myocardial infarction in men: prospective nested case-control study. BMJ. 1999;319:487–488.[Free Full Text]

93. Schmidt H, Schmidt R, Niederkorn K, Gradert GA, Schumacher M, Watzinger N, Hartung HP, Kostner GM. Paraoxonase PON1 polymorphism Leu-Met54 is associated with carotid atherosclerosis: results of Austrian Stroke Prevention Study. Stroke. 1998;29:2043–2048.[Abstract/Free Full Text]

94. Schmidt R, Schmidt H, Fazekas F, Kapeller P, Roob G, Lechner A, Kostner GM, Hartung HP. MRI cerebral white matter lesions and paraoxonase PON1 polymorphisms: three-year follow-up of the Austrian Stroke Prevention Study. Arterioscler Thromb Vasc Biol. 2000;20:1811–1816.[Abstract/Free Full Text]

95. Blatter-Garin M-C, James RW, Dussoix P, Blanché H, Passa P, Froguel P, Ruiz J. Paraoxonase polymorphism Met-Leu 54 is associated with modified serum concentrations of the enzyme. J Clin Invest. 1997;99:62–66.[Medline] [Order article via Infotrieve]

96. Sanghera DK, Saha N, Kamboh MI. The codon 55 polymorphism of the paraoxonase 1 gene is not associated with risk of coronary heart disease in Asian Indians and Chinese. Atherosclerosis. 1998;136:217–223.[Medline] [Order article via Infotrieve]

97. Leviev I, James RW. Promoter polymorphisms of human paraoxonase PON1 gene and serum activities and concentrations. Arterioscler Thromb Vasc Biol. 2000;20:516–521.[Abstract/Free Full Text]

98. McElveen J, Mackness MI, Colley CM, Peard T, Warner S, Walker CH. Distribution of paraoxon hydrolysing activity in the serum of patients after myocardial infarction. Clin Chem. 1986;32:671–673.[Abstract/Free Full Text]

99. Ayub A, Mackness MI, Arrol S, Mackness B, Patel J, Durrington PN. Serum paraoxonase after myocardial infarction. Arterioscler Thromb Vasc Biol. 1999;19:330–335.[Abstract/Free Full Text]

100. Deleted in proof.

101. Mackness MI, Harty D, Bhatnagar D, Winocour PH, Arrol S, Ishola M, Durrington PN. Serum paraoxonase activity in familial hypercholesterolaemia and insulin-dependent diabetes mellitus. Atherosclerosis. 1991;86:193–199.[Medline] [Order article via Infotrieve]

102. Abbott CA, Mackness MI, Kumar S, Boulton AJM, Durrington PN. Serum paraoxonase activity, concentration, and phenotype distribution in diabetes mellitus and its relationship to serum lipids and lipoproteins. Arterioscler Thromb Vasc Biol. 1995;15:1812–1818.[Abstract/Free Full Text]

103. Mackness B, Mackness MI, Arrol S, Turkie W, Julier K, Abuashia B, Miller JE, Boulton AJM, Durrington PN. Serum paraoxonase (PON1) 55 and 192 polymorphism and paraoxonase activity and concentration in non-insulin dependent diabetes mellitus. Atherosclerosis. 1998;139:341–349.[Medline] [Order article via Infotrieve]

104. Ikeda Y, Suehiro T, Inoue M, Nakauchi Y, Morita T, Arii K, Hiroyuki I, Kumon Y, Hushimoto K. Serum paraoxonase activity and its relationship to diabetic complications in patients with non-insulin-dependent diabetes mellitus. Metabolism. 1998;47:598–602.[Medline] [Order article via Infotrieve]

105. Hasselwander O, McMaster D, Fogarty DG, Maxwell AP, Nichols DP, Young IS. Serum paraoxonase and platelet-activating factor acetylhydrolase in chronic renal failure. Clin Chem. 1998;44:179–181.[Free Full Text]

106. Paragh G, Seres I, Balogh Z, Varga Z, Kárpáti I, Mátyas J, Ujhelyi L, Kakuk G. The serum paraoxonase activity in patients with chronic renal failure and hyperlipedemia. Nephron. 1998;80:166–170.[Medline] [Order article via Infotrieve]

107. Dautoine TF, Debord J, Charmes JP, Merle L, Marquet P, Lachatre G, Leroux-Robert C. Decrease of serum paraoxonase activity in chronic renal failure. J Am Soc Nephrol. 1998;9:2082–2088.[Abstract]

108. Patel BN, Mackness MI, Harty DW, Arrol S, Boot-Handford RP, Durrington PN. Serum esterase activities and hyperlipidaemia in the streptozotocin-diabetic rat. Biochim Biophys Acta. 1990;1035:113–116.[Medline] [Order article via Infotrieve]

109. Mackness B, Hunt R, Durrington PN, Mackness MI. Increased immunolocalisation of paraoxonase, clusterin and apolipoprotein AI in the human artery wall with progression of atherosclerosis. Arterioscler Thromb Vasc Biol. 1997;17:1233–1238.[Abstract/Free Full Text]

110. Aviram M, Hardak E, Vaya J, Mahmood S, Milo S, Hoffmann A, Billicke S, Draganov D, Rosenblat M. Human serum paraoxonases (PON1) Q and R selectively decrease lipid peroxides in human coronary and carotid atherosclerotic lesions: PON1 esterase and peroxide-like activities. Circulation. 2000;101:2510–2517.[Abstract/Free Full Text]

111. Aviram M, Rosenblat M, Bisgaier CL, Newton RS. Atorvastatin and gemfibrozil metabolites, but not the parent drugs are potent antioxidants against lipoprotein oxidation. Atherosclerosis. 1998;138:271–280.[Medline] [Order article via Infotrieve]

112. Paragh G, Balogh Z, Seres I, Harangi M, Boda J, Kovacs P. Effect of gemfibrozil on HDL-associated serum paraoxonase activity and lipoprotein profile in patients with hyperlipidaemia. Clin Drug Invest. 2000;19:277–282.

113. Durrington PN, Mackness MI, Bhatnagar D, Julier K, Prais H, Arrol S, Morgan J, Wood GNI. Effects of two different fibric acid derivatives on lipoproteins, cholesteryl ester transfer, fibrinogen, plasminogen activator inhibitor and paraoxonase activity in type IIb hyperlipoproteinaemia. Atherosclerosis. 1998;138:217–225.[Medline] [Order article via Infotrieve]

114. Turag J, Grniakova V, Valka J. Changes in paraoxonase and apolipoprotein A-I, B, C-III and E in subjects with combined familiar hyperlipoproteinaemia treated with ciprofibrate. Drugs Exp Clin Res. 2000;26:83–88.[Medline] [Order article via Infotrieve]

115. Tomas M, Senti M, Garcia-Faria F, Vila J, Torrents A, Covas M, Marrugat J. Effect of simvastatin therapy on paraoxonase activity and related lipoproteins in familial hypercholesterolaemic patients. Arterioscler Thromb Vasc Biol. 2000;20:2113–2119.[Abstract/Free Full Text]

116. Hayek T, Fuhrman B, Vaya J, Rosenblat M, Belinky P, Coleman R, Elis A, Aviram M. Reduced progression of atherosclerosis in apolipoprotein E deficient mice following consumption of red wine, or its polyphenols quercetin or catechin, is associated with reduced susceptibility of LDL to oxidation and aggregation. Arterioscler Thromb Vasc Biol. 1997;17:2744–2752.[Abstract/Free Full Text]

117. La Du BN. Human serum paraoxonase/arylesterase. In: Kalow W, ed. Pharmacogenetics of Drug Metabolism. New York, NY: Pergamon Press; 1992:51–91.

118. Haley RW, Marshall WW, McDonald GG, Daugherty MA, Petey F, Fleckenstein JL. Brain abnormalities in Gulf War syndrome: evaluation with 39 NMR spectroscopy. Radiology. 2000;215:807–817.[Abstract/Free Full Text]

119. Kao Y-L, Donaghue K, Chan A, Knight J, Silink A. A variant of paraoxonase (PON1) gene is associated with diabetic retinopathy in IDDM. J Clin Endocrinol Metab. 1998;83:2589–2592.[Abstract/Free Full Text]

120. Akhmedova S, Anisimov S, Yakimovsky A, Schwartz E. GlnArg 191 polymorphism of paraoxonase and Parkinson’s disease. Hum Hered. 1999;49:178–180.[Medline] [Order article via Infotrieve]

121. Konda I, Yamamoto M. Genetic polymorphism of paraoxonase 1 (PON1) and susceptibility to Parkinson’s disease. Brain Res. 1998;806:271–273.[Medline] [Order article via Infotrieve]

This article has been cited by other articles:

				L. Lavie and P. Lavie Molecular mechanisms of cardiovascular disease in OSAHS: the oxidative stress link Eur. Respir. J., June 1, 2009; 33(6): 1467 - 1484. [Abstract] [Full Text] [PDF]

				F. F. Verit, A. Verit, H. Ciftci, O. Erel, and H. Celik Paraoxonase-1 Activity in Subfertile Men and Relationship to Sperm Parameters J Androl, March 1, 2009; 30(2): 183 - 189. [Abstract] [Full Text] [PDF]

				M. L.E. MacDonald, M. van Eck, R. B. Hildebrand, B. W.C. Wong, N. Bissada, P. Ruddle, A. Kontush, H. Hussein, M. A. Pouladi, M. J. Chapman, et al. Despite Antiatherogenic Metabolic Characteristics, SCD1-Deficient Mice Have Increased Inflammation and Atherosclerosis Arterioscler. Thromb. Vasc. Biol., March 1, 2009; 29(3): 341 - 347. [Abstract] [Full Text] [PDF]

				E Matsuura and L. Lopez Autoimmune-mediated atherothrombosis Lupus, October 1, 2008; 17(10): 879 - 888. [Abstract] [PDF]

				G. Lurie, L. R. Wilkens, P. J. Thompson, K. E. McDuffie, M. E. Carney, K. Y. Terada, and M. T. Goodman Genetic Polymorphisms in the Paraoxonase 1 Gene and Risk of Ovarian Epithelial Carcinoma Cancer Epidemiol. Biomarkers Prev., August 1, 2008; 17(8): 2070 - 2077. [Abstract] [Full Text] [PDF]

				M. V. Poulakou, K. I. Paraskevas, I. S. Vlachos, S.-A. P. Karabina, M. R. Wilson, D. C. Iliopoulos, S. I. Tsitsilonis, D. P. Mikhailidis, and D. N. Perrea Effect of Statins on Serum Apolipoprotein J and Paraoxonase-1 Levels in Patients With Ischemic Heart Disease Undergoing Coronary Angiography Angiology, May 1, 2008; 59(2): 137 - 144. [Abstract] [PDF]

				T. Bhattacharyya, S. J. Nicholls, E. J. Topol, R. Zhang, X. Yang, D. Schmitt, X. Fu, M. Shao, D. M. Brennan, S. G. Ellis, et al. Relationship of Paraoxonase 1 (PON1) Gene Polymorphisms and Functional Activity With Systemic Oxidative Stress and Cardiovascular Risk JAMA, March 19, 2008; 299(11): 1265 - 1276. [Abstract] [Full Text] [PDF]

				S. Lavi, J. P. McConnell, R. Lavi, G. W. Barsness, C. S. Rihal, G. D. Novak, L. O. Lerman, and A. Lerman Association Between the Paraoxonase-1 192Q>R Allelic Variant and Coronary Endothelial Dysfunction in Patients With Early Coronary Artery Disease Mayo Clin. Proc., February 1, 2008; 83(2): 158 - 164. [Abstract] [Full Text] [PDF]

				F. F. Verit, O. Erel, and N. Celik Serum paraoxonase-1 activity in women with endometriosis and its relationship with the stage of the disease Hum. Reprod., January 1, 2008; 23(1): 100 - 104. [Abstract] [Full Text] [PDF]

				V. Charlton-Menys and P. N. Durrington Human cholesterol metabolism and therapeutic molecules Exp Physiol, January 1, 2008; 93(1): 27 - 42. [Abstract] [Full Text] [PDF]

				V. Charlton-Menys, L. Pisciotta, P. N. Durrington, R. Neary, C. D. Short, L. Calabresi, S. Calandra, and S. Bertolini Molecular characterization of two patients with severe LCAT deficiency Nephrol. Dial. Transplant., August 1, 2007; 22(8): 2379 - 2382. [Full Text] [PDF]

				R. S. Rector, S. O. Warner, Y. Liu, P. S. Hinton, G. Y. Sun, R. H. Cox, C. S. Stump, M. H. Laughlin, K. C. Dellsperger, and T. R. Thomas Exercise and diet induced weight loss improves measures of oxidative stress and insulin sensitivity in adults with characteristics of the metabolic syndrome Am J Physiol Endocrinol Metab, August 1, 2007; 293(2): E500 - E506. [Abstract] [Full Text] [PDF]

				T. M. Morgan, H. M. Krumholz, R. P. Lifton, and J. A. Spertus Nonvalidation of Reported Genetic Risk Factors for Acute Coronary Syndrome in a Large-Scale Replication Study JAMA, April 11, 2007; 297(14): 1551 - 1561. [Abstract] [Full Text] [PDF]

				J. W. Stephens, D. R. Gable, S. J. Hurel, G. J. Miller, J. A. Cooper, and S. E. Humphries Increased Plasma Markers of Oxidative Stress Are Associated with Coronary Heart Disease in Males with Diabetes Mellitus and with 10-Year Risk in a Prospective Sample of Males Clin. Chem., March 1, 2006; 52(3): 446 - 452. [Abstract] [Full Text] [PDF]

				V. Charlton-Menys, Y. Liu, and P. N. Durrington Semiautomated Method for Determination of Serum Paraoxonase Activity Using Paraoxon as Substrate Clin. Chem., March 1, 2006; 52(3): 453 - 457. [Abstract] [Full Text] [PDF]

				P. M. Erlich, K. L. Lunetta, L. A. Cupples, M. Huyck, R. C. Green, C. T. Baldwin, L. A. Farrer, and for the MIRAGE Study Group Polymorphisms in the PON gene cluster are associated with Alzheimer disease Hum. Mol. Genet., January 1, 2006; 15(1): 77 - 85. [Abstract] [Full Text] [PDF]

				J. Delgado Alves, L. J. Mason, P. R. J. Ames, P. P. Chen, J. Rauch, J. S. Levine, R. Subang, and D. A. Isenberg Antiphospholipid antibodies are associated with enhanced oxidative stress, decreased plasma nitric oxide and paraoxonase activity in an experimental mouse model Rheumatology, October 1, 2005; 44(10): 1238 - 1244. [Abstract] [Full Text] [PDF]

				K P Burdon, C D Langefeld, S R Beck, L E Wagenknecht, J J Carr, B I Freedman, D Herrington, and D W Bowden Association of genes of lipid metabolism with measures of subclinical cardiovascular disease in the Diabetes Heart Study J. Med. Genet., September 1, 2005; 42(9): 720 - 724. [Abstract] [Full Text] [PDF]

				D. L. Lucas, R. A. Brown, M. Wassef, and T. D. Giles Alcohol and the Cardiovascular System: Research Challenges and Opportunities J. Am. Coll. Cardiol., June 21, 2005; 45(12): 1916 - 1924. [Abstract] [Full Text] [PDF]

				D. I. Draganov, J. F. Teiber, A. Speelman, Y. Osawa, R. Sunahara, and B. N. La Du Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities J. Lipid Res., June 1, 2005; 46(6): 1239 - 1247. [Abstract] [Full Text] [PDF]

				W. Li, T. Asagami, H. Matsushita, K.-H. Lee, and P. S. Tsao Rosuvastatin Attenuates Monocyte-Endothelial Cell Interactions and Vascular Free Radical Production in Hypercholesterolemic Mice J. Pharmacol. Exp. Ther., May 1, 2005; 313(2): 557 - 562. [Abstract] [Full Text] [PDF]

				J. F. Teiber, D. I. Draganov, and B. N. La Du Purified human serum PON1 does not protect LDL against oxidation in the in vitro assays initiated with copper or AAPH J. Lipid Res., December 1, 2004; 45(12): 2260 - 2268. [Abstract] [Full Text] [PDF]

				B. Hansel, P. Giral, E. Nobecourt, S. Chantepie, E. Bruckert, M. J. Chapman, and A. Kontush Metabolic Syndrome Is Associated with Elevated Oxidative Stress and Dysfunctional Dense High-Density Lipoprotein Particles Displaying Impaired Antioxidative Activity J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 4963 - 4971. [Abstract] [Full Text] [PDF]

				S Karakucuk, G Baskol, A O Oner, M Baskol, E Mirza, and M Ustdal Serum paraoxonase activity is decreased in the active stage of Behcet's disease Br. J. Ophthalmol., October 1, 2004; 88(10): 1256 - 1258. [Abstract] [Full Text] [PDF]

				A. J. Lusis, A. M. Fogelman, and G. C. Fonarow Genetic Basis of Atherosclerosis: Part I: New Genes and Pathways Circulation, September 28, 2004; 110(13): 1868 - 1873. [Full Text] [PDF]

				M.-L. Liu, K. Ylitalo, R. Salonen, J. T. Salonen, and M.-R. Taskinen Circulating Oxidized Low-Density Lipoprotein and Its Association With Carotid Intima-Media Thickness in Asymptomatic Members of Familial Combined Hyperlipidemia Families Arterioscler. Thromb. Vasc. Biol., August 1, 2004; 24(8): 1492 - 1497. [Abstract] [Full Text] [PDF]

				G. Ferretti, T. Bacchetti, D. Busni, R. A. Rabini, and G. Curatola Protective Effect of Paraoxonase Activity in High-Density Lipoproteins against Erythrocyte Membranes Peroxidation: A Comparison between Healthy Subjects and Type 1 Diabetic Patients J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2957 - 2962. [Abstract] [Full Text] [PDF]

				A. Kontush, E. C. de Faria, S. Chantepie, and M. J. Chapman Antioxidative Activity of HDL Particle Subspecies Is Impaired in Hyperalphalipoproteinemia: Relevance of Enzymatic and Physicochemical Properties Arterioscler. Thromb. Vasc. Biol., March 1, 2004; 24(3): 526 - 533. [Abstract] [Full Text]

				B. Voetsch and J. Loscalzo Genetic Determinants of Arterial Thrombosis Arterioscler. Thromb. Vasc. Biol., February 1, 2004; 24(2): 216 - 229. [Abstract] [Full Text]

				W. H. F. Sutherland, S. A. de Jong, and R. J. Walker Hypochlorous acid and low serum paraoxonase activity in haemodialysis patients: an in vitro study Nephrol. Dial. Transplant., January 1, 2004; 19(1): 75 - 82. [Abstract] [Full Text] [PDF]

				M. Rosenblat, T. Hayek, K. Hussein, and M. Aviram Decreased Macrophage Paraoxonase 2 Expression in Patients With Hypercholesterolemia Is the Result of Their Increased Cellular Cholesterol Content: Effect of Atorvastatin Therapy Arterioscler. Thromb. Vasc. Biol., January 1, 2004; 24(1): 175 - 180. [Abstract] [Full Text] [PDF]

				J. E Upritchard, C. R. Schuurman, A. Wiersma, L. B. Tijburg, S. A. Coolen, P. J Rijken, and S. A Wiseman Spread supplemented with moderate doses of vitamin E and carotenoids reduces lipid peroxidation in healthy, nonsmoking adults Am. J. Clinical Nutrition, November 1, 2003; 78(5): 985 - 992. [Abstract] [Full Text] [PDF]

				S. Deakin, I. Leviev, S. Guernier, and R. W. James Simvastatin Modulates Expression of the PON1 Gene and Increases Serum Paraoxonase: A Role for Sterol Regulatory Element-Binding Protein-2 Arterioscler. Thromb. Vasc. Biol., November 1, 2003; 23(11): 2083 - 2089. [Abstract] [Full Text] [PDF]

				R. J. Hillstrom, A. K. Yacapin-Ammons, and S. M. Lynch Vitamin C Inhibits Lipid Oxidation in Human HDL J. Nutr., October 1, 2003; 133(10): 3047 - 3051. [Abstract] [Full Text] [PDF]

				A. Kontush, S. Chantepie, and M. J. Chapman Small, Dense HDL Particles Exert Potent Protection of Atherogenic LDL Against Oxidative Stress Arterioscler. Thromb. Vasc. Biol., October 1, 2003; 23(10): 1881 - 1888. [Abstract] [Full Text] [PDF]

				B. Voetsch Paraoxonase (PON1) in Health and Disease: Basic and Clinical Aspects International Journal of Toxicology, July 1, 2003; 22(4): 329 - 331. [PDF]

				B. Mackness, P. Durrington, P. McElduff, J. Yarnell, N. Azam, M. Watt, and M. Mackness Low Paraoxonase Activity Predicts Coronary Events in the Caerphilly Prospective Study Circulation, June 10, 2003; 107(22): 2775 - 2779. [Abstract] [Full Text] [PDF]

				A. Rigotti, H. E. Miettinen, and M. Krieger The Role of the High-Density Lipoprotein Receptor SR-BI in the Lipid Metabolism of Endocrine and Other Tissues Endocr. Rev., June 1, 2003; 24(3): 357 - 387. [Abstract] [Full Text] [PDF]

				S. Kopprasch, J. Pietzsch, E. Kuhlisch, and J. Graessler Lack of Association between Serum Paraoxonase 1 Activities and Increased Oxidized Low-Density Lipoprotein Levels in Impaired Glucose Tolerance and Newly Diagnosed Diabetes Mellitus J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1711 - 1716. [Abstract] [Full Text] [PDF]

				V. G. Cabana, C. A. Reardon, N. Feng, S. Neath, J. Lukens, and G. S. Getz Serum paraoxonase: effect of the apolipoprotein composition of HDL and the acute phase response J. Lipid Res., April 1, 2003; 44(4): 780 - 792. [Abstract] [Full Text] [PDF]

				A. Mertens, P. Verhamme, J. K. Bielicki, M. C. Phillips, R. Quarck, W. Verreth, D. Stengel, E. Ninio, M. Navab, B. Mackness, et al. Increased Low-Density Lipoprotein Oxidation and Impaired High-Density Lipoprotein Antioxidant Defense Are Associated With Increased Macrophage Homing and Atherosclerosis in Dyslipidemic Obese Mice: LCAT Gene Transfer Decreases Atherosclerosis Circulation, April 1, 2003; 107(12): 1640 - 1646. [Abstract] [Full Text] [PDF]

				M. Rosenblat, D. Draganov, C. E. Watson, C. L. Bisgaier, B. N. La Du, and M. Aviram Mouse Macrophage Paraoxonase 2 Activity Is Increased Whereas Cellular Paraoxonase 3 Activity Is Decreased Under Oxidative Stress Arterioscler. Thromb. Vasc. Biol., March 1, 2003; 23(3): 468 - 474. [Abstract] [Full Text] [PDF]

				O. Rozenberg, D. M. Shih, and M. Aviram Human Serum Paraoxonase 1 Decreases Macrophage Cholesterol Biosynthesis: Possible Role for Its Phospholipase-A2-Like Activity and Lysophosphatidylcholine Formation Arterioscler. Thromb. Vasc. Biol., March 1, 2003; 23(3): 461 - 467. [Abstract] [Full Text] [PDF]

				G. K. Marathe, G. A. Zimmerman, and T. M. McIntyre Platelet-activating Factor Acetylhydrolase, and Not Paraoxonase-1, Is the Oxidized Phospholipid Hydrolase of High Density Lipoprotein Particles J. Biol. Chem., January 31, 2003; 278(6): 3937 - 3947. [Abstract] [Full Text] [PDF]

				R. van Haperen, A. van Tol, T. van Gent, L. Scheek, P. Visser, A. van der Kamp, F. Grosveld, and R. de Crom Increased Risk of Atherosclerosis by Elevated Plasma Levels of Phospholipid Transfer Protein J. Biol. Chem., December 6, 2002; 277(50): 48938 - 48943. [Abstract] [Full Text] [PDF]

				D. P. Agarwal CARDIOPROTECTIVE EFFECTS OF LIGHT-MODERATE CONSUMPTION OF ALCOHOL: A REVIEW OF PUTATIVE MECHANISMS Alcohol Alcohol., September 1, 2002; 37(5): 409 - 415. [Abstract] [Full Text] [PDF]

				H. Jakubowski Homocysteine Is a Protein Amino Acid in Humans. IMPLICATIONS FOR HOMOCYSTEINE-LINKED DISEASE J. Biol. Chem., August 16, 2002; 277(34): 30425 - 30428. [Abstract] [Full Text] [PDF]

				P.N. Durrington, B. Mackness, and M.I. Mackness The Hunt for Nutritional and Pharmacological Modulators of Paraoxonase Arterioscler. Thromb. Vasc. Biol., August 1, 2002; 22(8): 1248 - 1250. [Full Text] [PDF]

				T. Satoh, P. Taylor, W. F. Bosron, S. P. Sanghani, M. Hosokawa, and B. N. L. Du Current Progress on Esterases: From Molecular Structure to Function Drug Metab. Dispos., May 1, 2002; 30(5): 488 - 493. [Abstract] [Full Text] [PDF]

				S. S. Levinson High Density- and Beta-Lipoprotein Screening for Risk of Coronary Artery Disease in the Context of New Findings on Reverse Cholesterol Transport Ann. Clin. Lab. Sci., April 1, 2002; 32(2): 123 - 136. [Abstract] [Full Text] [PDF]

				D. S. Ng, G. F. Maguire, J. Wylie, A. Ravandi, W. Xuan, Z. Ahmed, M. Eskandarian, A. Kuksis, and P. W. Connelly Oxidative Stress Is Markedly Elevated in Lecithin:Cholesterol Acyltransferase-deficient Mice and Is Paradoxically Reversed in the Apolipoprotein E Knockout Background in Association with a Reduction in Atherosclerosis J. Biol. Chem., March 29, 2002; 277(14): 11715 - 11720. [Abstract] [Full Text] [PDF]

				T. M. Forte, G. Subbanagounder, J. A. Berliner, P. J. Blanche, A. O. Clermont, Z. Jia, M. N. Oda, R. M. Krauss, and J. K. Bielicki Altered activities of anti-atherogenic enzymes LCAT, paraoxonase, and platelet-activating factor acetylhydrolase in atherosclerosis-susceptible mice J. Lipid Res., March 1, 2002; 43(3): 477 - 485. [Abstract] [Full Text] [PDF]

				M. M. Murphy, E. Vilella, S. Ceruelo, L. Figuera, M. Sanchez, J. Camps, G. Cuco, N. Ferre, A. Labad, N. Tasevska, et al. The MTHFR C677T, APOE, and PON55 Gene Polymorphisms Show Relevant Interactions with Cardiovascular Risk Factors Clin. Chem., February 1, 2002; 48(2): 372 - 375. [Full Text] [PDF]

				C. J. Ng, D. J. Wadleigh, A. Gangopadhyay, S. Hama, V. R. Grijalva, M. Navab, A. M. Fogelman, and S. T. Reddy Paraoxonase-2 Is a Ubiquitously Expressed Protein with Antioxidant Properties and Is Capable of Preventing Cell-mediated Oxidative Modification of Low Density Lipoprotein J. Biol. Chem., November 21, 2001; 276(48): 44444 - 44449. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Durrington, P. N. Articles by Mackness, M. I. Search for Related Content PubMed PubMed Citation Articles by Durrington, P. N. Articles by Mackness, M. I. Related Collections Pathophysiology Genetics of cardiovascular disease Lipid and lipoprotein metabolism Oxidant stress