© 1996 American Heart Association, Inc.
Articles |
Paraoxonase Genotypes, Lipoprotein Lipase Activity, and HDL
the Divisions of Metabolism, Endocrinology, and Nutrition (D.N.N., A.Z., J.E.H., J.D.B.), and Medical Genetics (C.E.F., R.J.R., R.H.), Department of Medicine, School of Medicine, and the Department of Epidemiology, School of Public Health and Community Medicine (J.E.H.), University of Washington.
Correspondence to John D. Brunzell, MD, University of Washington, Endocrinology/Metabolism, Box 356426, Seattle, WA 98195-6426. E-mail brunzell@u.washington.edu.
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Abstract |
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Paraoxonase, an enzyme associated with the high density lipoprotein (HDL) particle, hydrolyzes paraoxon, the active metabolite of the insecticide parathion. Several studies have shown that paraoxonase levels in humans have a distribution characteristic of two alleles, one with low activity and the other with high activity. Paraoxonase also has arylesterase activity, which does not exhibit activity polymorphism and can therefore serve as an estimate of enzyme protein. Although the ability of paraoxon to irreversibly inhibit lipoprotein lipase (LPL) has been exploited experimentally for many years, the role of plasma paraoxonase in lipoprotein metabolism is unknown. Seventy-two normal individuals were examined for paraoxonase genotypes, plasma paraoxonase and arylesterase activities, postheparin LPL and hepatic lipase (HL) activities, and lipoprotein levels to determine whether (1) paraoxonase activity or genotype determines lipoprotein levels via an effect on LPL or HL activity or (2) variation in LPL and HL activities determines HDL levels and indirectly affects paraoxonase activity and protein levels in plasma. In the entire group, paraoxonase activity was related to arylesterase activity and genotype. Whereas arylesterase activity was correlated with HDL cholesterol (HDL-C) and apolipoproteinA-I (apoA-I) levels, neither arylesterase nor paraoxonase was correlated with LPL or HL activity. Furthermore, LPL activity was positively correlated and HL inversely correlated with HDL cholesterol and apoA-I levels, whereas LPL was inversely correlated with triglyceride levels. The paraoxonase genotypes of the study group were 30 individuals homozygous for the low-activity allele, 38 heterozygotes, and 4 individuals homozygous for the high-activity allele. Paraoxonase genotype accounted for
.75 of the variation in paraoxonase activity. Paraoxonase activity was linearly related to arylesterase activity within each subgroup. No difference in either LPL or HL activity was seen as a function of paraoxonase genotype, nor were differences seen in plasma triglyceride or HDL-C by genotype by ANOVA. The relation between LPL and HL and components of HDL in the paraoxonase genotypic subgroups in general reflected the associations seen in the group as a whole. Multivariate analysis showed that LPL, HL, and arylesterase, a measure of paraoxonase mass, were independent predictors of HDL cholesterol, while paraoxonase genotype or activity was not. Thus, variation in LPL and HL appears to be significantly related to HDL cholesterol and apoA-I levels. The levels of HDL are a major correlate of paraoxonase protein levels, while paraoxonase genotype is the major predictor of plasma paraoxonase activity.
Key Words: arylesterase • paraoxon • hepatic lipase • apolipoproteinA-I • apolipoproteinA-II
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Introduction |
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Paraoxonase hydrolyzes paraoxon, the active metabolite of the insecticide parathion. Parathion is toxic to humans because of its irreversible inhibition of acetyl cholinesterase. Paraoxonase activity was identified in human plasma more than 40 years ago,1 and it exhibits substrate-dependent activity polymorphism in humans,2 3 in whom one isoform hydrolyzes paraoxon with a high turnover number (specific activity) and the other with a low turnover number. Both isoforms of the protein have arylesterase activity, which hydrolyzes other substrates such as phenylacetate or chlorpyrifos oxon (the active metabolite of chlorpyrifos) with the same turnover number and therefore does not exhibit substrate-dependent activity polymorphism. It has been proposed that high levels of paraoxonase provide individuals protection against inhibition of cholinesterase by toxic organophosphate substrates of the enzyme.3
Two alleles for the paraoxonase gene encode low and high enzyme–activity forms.4 The cDNA for human paraoxonase has been cloned5 and the molecular basis of its polymorphism elucidated.6 7 The amino acid Arg at position 192 of the protein6 (the same as position 191 by the numbering system of Adkins et al7 ) specifies high-activity paraoxonase, whereas Gln at this position specifies low-activity paraoxonase. A second polymorphism (Leu/Met) at position 55 does not affect the catalytic activity of paraoxonase.
Saha et al8 have reported that individuals with high paraoxonase activity have elevations in plasma TG and reductions in HDL-C. It is possible that changes in plasma TG and HDL-C levels might be related to paraoxonase activity, since paraoxon is an extremely effective irreversible inactivator of LPL and HL.9 Paraoxonase activity has also been reported to be low in patients with insulin-dependent diabetes mellitus and familial hypercholesterolemia.10 Although paraoxonase activity has been reported in HDL,11 12 13 the role of paraoxonase in lipid transport and metabolism is unknown. Most plasma paraoxonase is bound to large apoA-I without apoA-II HDL particles,14 15 but some HDL-containing paraoxonase appears to contain apo-J as well.14 16 The physiological mechanisms accounting for the heterogeneity of HDL-containing paraoxonase as well as the natural substrate for human paraoxonase remain to be determined.
A relationship among paraoxonase, HDL, and LPL might be that paraoxonase hydrolyzes a physiological substrate in plasma that affects LPL and HL activity and thus lipoprotein metabolism. Alternatively, LPL and HL might be determinants of HDL levels, and because paraoxonase is bound to HDL, determinants of the amount of paraoxonase protein in plasma. In this study these two possibilities were investigated in normal individuals to determine the probable mechanism relating paraoxonase genotype and activity, LPL, HL and HDL.
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Methods |
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The 72 subjects recruited for this study responded to advertisements for normal volunteers according to Human Subjects Review Committee Guidelines as described previously.17 In brief, blood samples from fasting volunteers were drawn before and 10 minutes after an intravenous bolus of 60 U/kg heparin. Blood was immediately chilled on ice and centrifuged, and 1-mL aliquots of plasma were frozen at -70°C. Total cholesterol, HDL-C, TG, and calculated LDL-C levels were measured in fresh, preheparin EDTA-plasma by methods in use at the Northwest Lipid Research Laboratories. ApoB, apoA-I, and apoA-II were measured according to published methods.18 Postheparin plasma LPL and HL assays were performed as previously described.19
Paraoxonase and arylesterase activities were measured according to the method of Furlong et al20 on 1-mL aliquots of fasting lithium-heparin-plasma that had been stored at -70°C. Purified paraoxon was obtained from ICN K&K and chlorpyrifos oxon from Dow Chemical Co. Paraoxonase activity was measured spectrophotometrically by monitoring the formation of p-nitrophenol at 405 nm. Arylesterase activity was measured by hydrolysis of phenylacetate (a nonpolymorphic substrate of paraoxonase) and monitoring the formation of phenol.3 11 The paraoxonase and arylesterase assays were each done in duplicate. Nineteen individuals were sampled twice, 6 months apart, with repeated paraoxonase and arylesterase assays. The intraindividual coefficient of variation for replicate analyses was 13.4% for paraoxonase and 7.0% for arylesterase.21
To confirm correct assignment of the paraoxonase alleles, particularly heterozygous versus homozygous-high individuals with high paraoxonase levels, genomic DNA was isolated from 71 of 72 subjects for whom frozen buffy coats were available.22 PCR was performed with the primers described in Humbert et al6 on a Perkin-Elmer Thermal Cycler. These primers flank a restriction site polymorphism for Alw I at position Arg192 in the high-activity allele. PCR products were generated according to previously described cycling parameters with slight modification: 4 minutes at 94°C, followed by 35 cycles at 94°C for 30 seconds and 61°C for 1 minute, and finally 7 minutes at 72°C. The PCR products were precipitated with ethanol, digested with Alw I (New England Biolabs), electrophoresed on 10% polyacrylamide gels, stained with ethidium bromide, and photographed.
Data were analyzed with unpaired t tests, ANOVA, linear regression, and multiple linear regression. Significance was defined at P<.05. Graphs and tables were prepared with SigmaPlot and SigmaStat software (Jandel Scientific).
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Results |
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The study population consisted of 72 individuals (mean age, 34 years) and included 41 females and 31 males. All of these individuals had plasma total cholesterol, LDL-C, TG, and HDL-C levels that fell within the normal range based on the Lipid Research Clinics Prevalence Study.23 Ninety-two percent of subjects were white and 8% Asian or black.
Paraoxonase activity was distributed trimodally, consistent with the two known codominant alleles that confer high and low activity, whereas arylesterase activity had a unimodal distribution. Since paraoxonase activity alone cannot reliably distinguish the three genotypes, paraoxonase activity was plotted against arylesterase activity, which does not exhibit polymorphism in its activity and therefore provides an accurate linear estimate of enzyme mass. Previous work has shown that paraoxonase activity and mass (by immunoblotting) in low-activity subjects show a uniform linear correlation.24 The paraoxonase versus arylesterase plot effectively separates homozygous-low individuals from heterozygotes and from homozygous-high individuals (Fig 1
). It should be mentioned that the distinction between heterozygotes and those who are homozygous-high is not completely reliable. The Alw I restriction site polymorphism in the paraoxonase gene was used to genotype all subjects for whom genomic DNA was available. The single subject for whom no genomic DNA was available had a paraoxonase activity of 401 U/L and an arylesterase activity of 147 U/mL, which placed him in the middle of the homozygous-low group (Fig 1). We identified 30 homozygous-low individuals, 38 heterozygotes, and 4 homozygous-high individuals on the basis of the combination of enzyme activity and restriction site polymorphism data. The homozygous-low group activity data perfectly matched the Alw I genotyping. More important, genotyping allowed resolution between heterozygotes and homozygous-high individuals. The Alw I restriction site polymorphism–defined homozygous-high individuals had paraoxonase activities that overlapped those of heterozygotes, so that no paraoxonase activity cutoff by itself could accurately separate these two subgroups. The ratio of paraoxonase activity to arylesterase activity substantially improved the classification, but one individual would have been misidentified as homozygous-high without genotyping.
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), heterozygotes (
), and homozygous-high (
). Correct assignment of homozygous-high and heterozygous individuals was confirmed by PCR genotyping. Linear regression lines are shown for each group.
The frequency of the low-activity allele was .68 and of the high-activity allele .32, in excellent agreement with earlier studies.20 25 The allele frequencies were in Hardy-Weinberg equilibrium (
2 =1.66, P=.44). Paraoxonase genotype accounted for .76 of the variation in paraoxonase activity level. Paraoxonase activity was linearly correlated with arylesterase activity within each genotypic subgroup. Linear regression of paraoxonase activity versus arylesterase activity in each subgroup was highly significant (homozygous-low r=.96, P<.0001; heterozygotes r=.72, P<.0001; homozygous-high r=.91, P=.05; Fig 1
).
When the study population was divided by paraoxonase genotype into three subgroups, as expected there were significant differences (P<.0001) in paraoxonase activity (Table 1). Paraoxonase activity was similar in males and females. LPL and HL activity values were not different (by ANOVA) in individuals with different paraoxonase genotypes. Lipoprotein and apolipoprotein levels were statistically similar (by ANOVA) across all three groups. When the data were examined by unpaired t tests, the homozygous-high subgroup (n=4) had significantly lower levels of total cholesterol, TG, apoB, and apoA-II compared with heterozygous or homozygous-low subgroups; otherwise the results of ANOVA and t tests were in agreement.
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Linear regression was used to examine the association of both paraoxonase activity and arylesterase activity, as an estimate of enzyme protein, with the various lipoproteins, apolipoproteins, and lipolytic enzymes in the entire study population. Arylesterase activity was associated with HDL-C (r=.31, P<.008) and apoA-I (r=.43, P<.001; Fig 2)and weakly with apoA-II (r=.24, P<.04). None of the HDL components was correlated with paraoxonase activity. LPL activity was correlated with HDL-C (r=.44, P<.003), apoA-I (r=.28, P<.02), and TG (r=-.42, P<.001) but not with apoA-II (r=.09). The relations between LPL activity and paraoxonase activity (r=.21, P=.076) and arylesterase activity (r=.08) were not significant. HL activity was inversely related to HDL-C (r=-.54, P<.001) and apoA-I (r=-.40, P<.001) but not to apoA-II (r=.11), paraoxonase activity, or arylesterase activity. No significant correlation was found between either paraoxonase (r=-.08) or arylesterase (r=-.06) activity and the LDL-C to HDL-C ratio.
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The relation of paraoxonase and arylesterase activities with lipoprotein and lipolytic activity measures within the homozygous-low subgroup was examined separately. Linear regression of HDL-C levels with paraoxonase activity (r=.50, P<.005) and arylesterase activity (r=.61, P<.001) were both highly significant (Fig 3). Similarly, apoA-I was correlated with paraoxonase activity (r=.50, P<.005) and arylesterase activity (r=.60, P<.001). No correlation was found between apoA-II and either paraoxonase activity or arylesterase activity. Plasma postheparin LPL activity was correlated with paraoxonase (r=.40, P<.03) and arylesterase (r=.42, P<.025) activity in the homozygous-low group (Fig 4), but no statistically significant relation was seen between postheparin HL activity and paraoxonase (r=-.15) or arylesterase (r=-0.20) activity. TG levels were not related to paraoxonase activity (r=-.30, P=.11) and only weakly related to arylesterase activity (r=-.36, P=.05), which is most likely due to the inverse relation of TG with HDL-C (r=-.55, P<.002) rather than a direct relation of arylesterase with TG. Neither paraoxonase (r=-.22) nor arylesterase (r=-.25) activity was significantly correlated with the LDL-C to HDL-C ratio.
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The heterozygous group (n=38) was analyzed both separately and together with the homozygous-high group (n=4). Since there were no differences in results, the data are reported for the two groups together. Unlike the homozygous-low group, neither paraoxonase activity nor arylesterase activity was correlated with HDL-C, apoA-I, or apoA-II. Neither LPL nor HL activity was related to either paraoxonase activity or arylesterase activity. Similar to the homozygous-low subgroup, LPL activity was positively related to HDL-C levels (r=.49, P<.001), and HL activity was related negatively (r=-.53, P<.001). Paraoxonase (r=-.06) and arylesterase (r=.14) activities were not significantly correlated with the LDL-C to HDL-C ratio.
To further investigate relations among paraoxonase genotype, paraoxonase activity, arylesterase activity, and HDL components (ie, HDL-C, apoA-I, and apoA-II), we performed multiple linear regression as shown in Table 2. In the model, arylesterase activity, LPL activity, and HL activity were independent predictors of HDL-C. Neither paraoxonase activity nor genotype were significant contributors to the model. The same relation was seen between these variables and apoA-I. In contrast, none of the variables except age was significantly related to apoA-II.
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No correlation was noted between either paraoxonase activity or arylesterase activity and total cholesterol, LDL-C, or apoB in the entire group or any subgroup.
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Discussion |
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In the present study the relation between paraoxonase and the lipolytic enzymes LPL and HL was examined. Two possibilities were explored. First, could variations in paraoxonase activity directly affect LPL and HL and thus lipid and lipoprotein levels? For example, low paraoxonase activity might allow accumulation of an as-yet-unidentified physiological substrate in plasma that might inhibit both LPL and HL activity, with resultant changes in TG levels, HDL levels, and lipoprotein composition. The second possibility was that both LPL and HL are major determinants of HDL concentration and composition.26 27 The level of a large, apoA-I–only HDL subspecies would then be one determinant of paraoxonase protein levels and, along with genotypic variation, of paraoxonase activity.
The present data support the second possibility that variations in LPL and HL affect paraoxonase through their independent effects on HDL levels. It is LPL and HL, bound to the vascular endothelium in the periphery and liver, that are released into the plasma because of intravenous heparin, that have these effects. Both LPL and HL were highly correlated with HDL levels, in agreement with what has been previously reported, and each is known to be a major determinant of HDL catabolism.26 27 Paraoxonase activity and arylesterase activity were also correlated with HDL-C and apoA-I levels, consistent with reports that this enzyme is bound to a large, apoA-I–containing HDL subspecies.14 The results of multivariate analyses add further support. In the multivariate models, paraoxonase protein level as represented by arylesterase activity level was associated with HDL-C and apoA-I, independent of LPL and HL activity, whereas paraoxonase genotype and activity were not. This finding supports the concept that plasma paraoxonase protein levels are correlated with the amount of carrier HDL particles, whereas paraoxonase activity is largely predicted by genotype.
Paraoxonase genotype determines .75 of the variation in paraoxonase activity. Other factors certainly affect paraoxonase activity levels, as evidenced by the wide variation in paraoxonase activity within each genotype subgroup (Fig 1). The HDL level is therefore likely to be one of several factors that account for this variation. One important factor is variation in enzyme mass, which could be due to differences in hepatic synthesis of paraoxonase. Differences in regulatory domains of the paraoxonase gene, separate from the activity polymorphism, could account for the differences in enzyme levels. Other genes may also control the synthesis and catabolism of paraoxonase bound to HDL. Effects of environmental factors such as diet, exercise, or medications are also unknown.
The finding that HDL and LPL activities are significantly related to paraoxonase activity in the homozygous-low genotype subgroup and not the other subgroups cannot be readily explained. This finding might suggest that the amount of paraoxonase activity contained on HDL could be limiting. Thus, the amount of paraoxonase available to inactivate a possible plasma inhibitor of LPL would be linearly related to plasma LPL activity below a threshold level. The heterozygous or homozygous-high subjects would have paraoxonase activity levels above this limiting threshold, so that no relation between LPL and paraoxonase activity would be seen in these two groups. Although all paraoxonase activity levels in the homozygous-low subgroup are below those of both the heterozygotes and homozygous-high subjects, the mean levels of LPL and HDL in all three groups were not significantly different (Table 1). As well, HL activity did not show any relation to paraoxonase activity in the homozygous-low subgroup. These latter observations argue against the threshold hypothesis. Whether a unique physical interaction between homozygous-low paraoxonase and HDL components is present and could then account for the relation with LPL and not HL is an interesting question that requires further investigation.
Variations in plasma paraoxonase activity have been reported to be associated with changes in plasma TG, HDL-C, and apoB levels.8 14 While the relation between paraoxonase and HDL may reflect enzyme binding to large HDL (with apoA-I),14 this would not account for the reported associations with plasma TG or apoB levels that others have reported. On further examination, a correlation between paraoxonase mass and apoA-I and HDL-C was confirmed, but no correlation with apoB was found.28 Hegele et al29 30 determined the paraoxonase genotype in a large, genetically isolated population of Hutterites in Canada and found that paraoxonase genotype variation accounted for 
.01 of the variation in lipoprotein concentrations. These reports did not measure paraoxonase activity, which can vary considerably more within genotypes, as shown in several other studies4 25 including the present report. The statistically important effect of paraoxonase genotype on lipoproteins was quantitatively small and would not be expected to be detected in the present study. Other variables, including LPL, HL, and cholesterol ester transfer protein, clearly are physiologically more important determinants of HDL levels than is paraoxonase genotype.31 Thus, HDL levels are correlated with and may be a major determinant of paraoxonase protein levels. Paraoxonase isoforms would contribute to variation in enzyme activity. Factors that affect HDL, such as LPL and HL, would be expected to indirectly affect paraoxonase activity via their effects on HDL level and composition.
The function of paraoxonase, if any, in lipoprotein metabolism remains an unanswered question. HDL can inhibit LDL oxidation in vitro32 and block the monocyte response caused by modified LDL.33 Platelet-activating factor-acetylhydrolase, an enzyme also associated with HDL, has been shown to block the formation of modified LDL.34 Paraoxonase associated with HDL may also protect LDL from oxidative stresses by a similar mechanism.35 36 One could hypothesize that variations in genetic and other determinants of the level of HDL-containing paraoxonase may be involved in the susceptibility of LDL to oxidation and predisposition to atherosclerosis.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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The study was supported in part by National Institutes of Health (NIH) grants HL-30086 (to Dr Brunzell) and ES-05194 (to Dr Furlong), Bethesda, Md. A portion of this study was performed at the University of Washington Medical Center Clinical Research Center (NIH grant RR-37. Dr Nevin was supported by NIH Physician-Scientist award HL-02162.
Received October 2, 1995;
revision received March 13, 1996;
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References |
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|---|
1. Aldridge WN. An enzyme hydrolysing diethyl p-nitrophenyl phosphate (E-600) and its identity with the A-esterase of mammalian sera. Biochem J. 1953;53:117-124.[Medline] [Order article via Infotrieve]
2. Eckerson HW, Wyte CM, La Du BN. The human paraoxonase/arylesterase polymorphism. Am J Hum Genet. 1983;35:1126-1138.[Medline] [Order article via Infotrieve]
3. Furlong CE, Richter RJ, Seidel SL, Motulsky AG. Role of genetic polymorphism of human plasma paraoxonase/arylesterase in hydrolysis of the insecticide metabolites chlorpyrifos oxon and paraoxon. Am J Hum Genet. 1988;43:230-238.[Medline] [Order article via Infotrieve]
4.
Playfer JR, Eze CL, Bullen MF, Evans DAP. Genetic polymorphism and interethnic variability of plasma paraoxonase activity. J Med Genet. 1976;13:337-342.
5. Hassett C, Richter RJ, Humbert R, Chapline C, Crabb JW, Omiecinski CJ, Furlong CE. Characterization of cDNA clones encoding rabbit and human serum paraoxonase: the mature protein retains its signal sequence. Biochemistry. 1991;30:10141-10149.[Medline] [Order article via Infotrieve]
6. Humbert R, Adler DA, Disteche CM, Hassett C, Omiecinski CJ, Furlong CE. The molecular basis of the human serum paraoxonase activity polymorphism. Nat Genet. 1993;3:73-76.[Medline] [Order article via Infotrieve]
7. Adkins S, Gan KN, Mody M, La Du BN. Molecular basis for the polymorphic forms of human serum paraoxon/arylesterase: Gln or Arg at position 191, for the respective A or B allozymes. Am J Hum Genet. 1993;52:598-608.[Medline] [Order article via Infotrieve]
8. Saha N, Roy AC, Teo SH, Tay JSH, Ratnam SS. Influence of serum paraoxonase polymorphism on serum lipids and apolipoproteins. Clin Genet. 1991;40:277-282.[Medline] [Order article via Infotrieve]
9. Rizack MA. Intravascular effect of heparin on plasma nonesterified fatty acid and triglyceride during alimentary lipemia. Proc Soc Exp Biol Med. 1960;104:111-113.
10. 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]
11. Kitchen BJ, Masters CJ, Winzor DJ. Effects of lipid removal on the molecular size and kinetic properties of bovine arylesterase. Biochem J. 1973;135:93-99.[Medline] [Order article via Infotrieve]
12. Don MM, Masters CJ, Winzor DJ. Further evidence for the concept of bovine plasma arylesterase as a lipoprotein. Biochem J. 1975;151:625-630.[Medline] [Order article via Infotrieve]
13. Mackness MI, Hallam SD, Peard T, Warner S, Walker CH. The separation of sheep and human serum "A"-esterase activity into the lipoprotein fraction by ultracentrifugation. Comp Biochem Physiol. 1985;82B:675-677.
14. 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-45: identity of K-45 with paraoxonase. Eur J Biochem. 1993;211:871-879.[Medline] [Order article via Infotrieve]
15.
Cheung MC, Albers JJ. Characterization of lipoprotein particles isolated by immunoaffinity chromatography: particles containing A-I and A-II and particles containing A-I but no A-II. J Biol Chem. 1984;259:12201-12209.
16. 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]
17.
Zambon A, Austin MA, Brown BG, Hokanson JE, Brunzell JD. Effect of hepatic lipase on LDL in normal men and those with coronary artery disease. Arterioscler Thromb. 1993;13:147-153.
18. Marcovina S, Albers JJ. International Federation of Clinical Chemistry study on the standardization of apoproteins A-I and B. Curr Opin Lipid. 1991;2:355-361.
19.
Iverius P-H, Brunzell JD. Human adipose tissue lipoprotein lipase: changes with feeding and relation to postheparin plasma. Am J Physiol. 1985;249:E107-E114.
20. Furlong CE, Richter RJ, Seidel SL, Costa LG, Motulsky AG. Spectrophotometric assays for the enzymatic hydrolysis of the active metabolites of chlorpyrifos and parathion by plasma paraoxonase/arylesterase. Anal Biochem. 1989;180:242-247.[Medline] [Order article via Infotrieve]
21.
Jacobs DR, Barrett-Conner E. Retest reliability of plasma cholesterol and triglyceride: the Lipid Research Clinics prevalence study. Am J Epidemiol. 1982;116:878-885.
22. Ponz M, Solowiejcky D, Harpel B, Mory Y, Swartz E, Surrey S. Construction of human gene libraries from small amounts of peripheral blood: analysis of B-like globin genes. Hemoglobin. 1982;6:27-36.[Medline] [Order article via Infotrieve]
23. Lipid Research Clinics Program. The Lipid Clinics Population Studies Data Book: the Prevalence Study. Bethesda, Md: National Institutes of Health; 1980;1:52-81.
24. Furlong CE, Costa LG, Hassett C, Richter RJ, Sundstrom JA, Adler DA, Disteche CM, Omiecinski CJ, Chapline C, Crabb JW, Humbert R. Human and rabbit paraoxonase: purification, cloning, sequencing, mapping and role of polymorphism in organophosphate detoxification. Chem Biol Interactions. 1993;87:35-48.[Medline] [Order article via Infotrieve]
25. Geldmacher-von Mallinckrodt M, Diepgen TL. The human serum paraoxonase-polymorphism and specificity. Toxicol Environ Chem. 1988;18:79-196.
26. Magill P, Rao SN, Miller NE, Nicoll A, Brunzell J, St Hilaire J, Lewis B. Relationships between the metabolism of high-density and very-low-density lipoproteins in man: studies of apolipoprotein kinetics and adipose tissue lipoprotein lipase activity. Eur J Clin Invest. 1982;12:113-120.[Medline] [Order article via Infotrieve]
27. Kuusi T, Ehnholm C, Viikari J, Harkonen R, Vartiainen E, Puska P, Taskinen M-R. Postheparin plasma lipoprotein and hepatic lipase are determinants of hypo- and hyperalphalipoproteinemia. J Lipid Res. 1989;30:1117-1126.[Abstract]
28. Blatter Garin M-C, Abbott C, Messmer S, Mackness M, Durrington P, Pometta D, James RW. Quantification of human serum paraoxonase by enzyme-linked immunoassay: population differences in protein concentrations. Biochem J. 1994;304:549-554.
29.
Hegele RA, Brunt JH, Connelly PW. A polymorphism of the paraoxonase gene associated with variation in plasma lipoproteins in a genetic isolate. Arterioscler Thromb Vasc Biol. 1995;15:89-85.
30.
Hegele RA, Brunt JH, Connelly PW. Multiple genetic determinants of variation of plasma lipoproteins in Alberta Hutterites. Arterioscler Thromb Vasc Biol. 1995;15:861-871.
31. Tall AR. Plasma high density lipoproteins: metabolism and relationship to atherogenesis. J Clin Invest. 1990;86:379-384.
32. Mackness MI, Arrol S, Abbott C, 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]
33. Navab M, Imes SS, Hama SY, Hough GP, Ross LA, Bork RW, Valente AJ, Berliner JA, Drinkwater DC, Laks H, Fogelman AM. 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.
34. Watson AD, Navab M, Hama SY, Sevenian A, Prescott SM, Stafforini DM, McIntyre TM, La Du BN, Fogelman AM, Berliner JA. Effect of platelet activating factor-acetylhydrolase on the formation and action of minimally oxidized-low density lipoprotein. J Clin Invest. 1995;95:774-782.
35.
Berliner JA, Navab M, Fogelman AM, Frank JS, Demer LL, Edwards PA, Watson AD, Lusis AJ. Atherosclerosis: basic mechanisms, oxidation, inflammation, and genetics. Circulation. 1995;91:2488-2496.
36. Watson AD, Berliner JA, Hama SY, La Du BN, Faull KF, Fogelman AM, Navab M. Protective effect of high density lipoprotein associated paraoxonase: inhibition of the biological activity of minimally oxidized low density lipoprotein. J Clin Invest. 1995;96:2882-2891.
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 N. Ferre, J. Camps, J. Fernandez-Ballart, V. Arija, M. M. Murphy, S. Ceruelo, E. Biarnes, E. Vilella, M. Tous, and J. Joven Regulation of Serum Paraoxonase Activity by Genetic, Nutritional, and Lifestyle Factors in the General Population Clin. Chem., September 1, 2003; 49(9): 1491 - 1497. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Cheung, S. D. Sibley, J. P. Palmer, J. F. Oram, and J. D. Brunzell Lipoprotein lipase and hepatic lipase: their relationship with HDL subspecies Lp(A-I) and Lp(A-I,A-II) J. Lipid Res., August 1, 2003; 44(8): 1552 - 1558. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. P. Jarvik, T. S. Hatsukami, C. Carlson, R. J. Richter, R. Jampsa, V. H. Brophy, S. Margolin, M. Rieder, D. Nickerson, G. D. Schellenberg, et al. Paraoxonase Activity, But Not Haplotype Utilizing the Linkage Disequilibrium Structure, Predicts Vascular Disease Arterioscler Thromb Vasc Biol, August 1, 2003; 23(8): 1465 - 1471. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. P. Jarvik, L. S. Rozek, V. H. Brophy, T. S. Hatsukami, R. J. Richter, G. D. Schellenberg, and C. E. Furlong Paraoxonase (PON1) Phenotype Is a Better Predictor of Vascular Disease Than Is PON1192 or PON155 Genotype Arterioscler Thromb Vasc Biol, November 1, 2000; 20(11): 2441 - 2447. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. J. Kudchodkar, A. G. Lacko, L. Dory, and T. V. Fungwe Dietary Fat Modulates Serum Paraoxonase 1 Activity in Rats J. Nutr., October 1, 2000; 130(10): 2427 - 2433. [Abstract] [Full Text]
|
|
|
|
|
|
S. Sen-Banerjee, X. Siles, and H. Campos Tobacco Smoking Modifies Association Between Gln-Arg192 Polymorphism of Human Paraoxonase Gene and Risk of Myocardial Infarction Arterioscler Thromb Vasc Biol, September 1, 2000; 20(9): 2120 - 2126. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Cao, A. Girard-Globa, F. Berthezene, and P. Moulin Paraoxonase protection of LDL against peroxidation is independent of its esterase activity towards paraoxon and is unaffected by the Q->R genetic polymorphism J. Lipid Res., January 1, 1999; 40(1): 133 - 139. [Abstract] [Full Text]
|
|
|
|
|
|
T. Zama, M. Murata, Y. Matsubara, K. Kawano, N. Aoki, H. Yoshino, G. Watanabe, K. Ishikawa, and Y. Ikeda A 192Arg 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, December 1, 1997; 17(12): 3565 - 3569. [Abstract] [Full Text]
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