Determinants of homocysteine-thiolactonase activity of the paraoxonase-1 (PON1) protein in humans.
Homocysteine (Hcy)-thiolactonase (HTase) activity of the paraoxonase-1 (PON1) protein detoxifies Hcy-thiolactone in human blood and could thus delay the development of atherosclerosis. To gain insight into physiological role(s) of the PON1 protein, we studied HTase activities and PON1 genotypes in a group of 184 subjects, 32.6% of whom were healthy, 27.7% had angiographically proven coronary artery disease but did not have myocardial infarction (CAD), and 39.7% had myocardial infarction (MI). We found that the hydrolytic activities of the serum PON1 protein towards Hcy-thiolactone and the organophosphate paraoxon substrates were strongly correlated. PON1-192-RR and PON1-55-LL genotypes were associated with high HTase activity. HTase activity was negatively correlated with age (beta = -0.135, p =0.002), plasma total Hcy (in 192-QR subjects only; r = -0.46, p = 0.001), and positively correlated with total cholesterol (beta = 0.169, p<0.001), but not with HDL cholesterol. Mean HTase activities were similar in CAD subjects, MI subjects, and in healthy controls. However, the frequency of the PON1-192-RR genotype tended to be lower in CAD subjects than in controls (2% vs 10.0%, p = 0.057) and higher in MI subjects that in CAD subjects (10.9% vs 2.0%, p = 0.001). The R-allele was marginally associated with CAD (26.7% in controls vs 17.6% in CAD, p = 0.146) and significantly associated with MI (17.6% in CAD vs 31.5% in MI, p = 0.018). Multiple regression analysis suggests that PON1 genotype, total Hcy, total cholesterol, and age are major determinants of HTase activity in humans.
Lacinski
M
M
Department of Microbiology and Molecular Genetics, UMDNJ-New Jersey Medical School, International Center for Public Health, Newark, NJ 07103, USA.
Skorupski
W
W
Cieslinski
A
A
Sokolowska
J
J
Trzeciak
W H
WH
Jakubowski
H
H
D000328:Adult; D000367:Age Factors; D000368:Aged; D000483:Alleles; D000792:Angiography; D001161:Arteriosclerosis / Q000378:metabolism; D043303:Aryldialkylphosphatase / Q000096:biosynthesis* / Q000737:chemistry* / Q000378:metabolism; D002265:Carboxylic Ester Hydrolases / Q000737:chemistry*; D002784:Cholesterol / Q000378:metabolism; D003324:Coronary Artery Disease / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006710:Homocysteine / Q000737:chemistry*; D006801:Humans; D007783:Lactones / Q000737:chemistry*; D050356:Lipid Metabolism; D008297:Male; D008875:Middle Aged; D008956:Models, Chemical; D009203:Myocardial Infarction / Q000235:genetics; D011110:Polymorphism, Genetic; D012044:Regression Analysis; D013997:Time Factors
D007783:Lactones; D006710:Homocysteine; D002784:Cholesterol; D002265:Carboxylic Ester Hydrolases; C502233:homocysteine-thiolactonase, human; D043303:Aryldialkylphosphatase