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Biomedical subjects

B Mackness

Publications and source records attributed to B Mackness.

26 records · Page 2Linked to original sources
PubMed1998

Human serum paraoxonase.

1. Human serum paraoxonase (PON1) is a Ca2+-dependent 45-kDa glycoprotein that is associated with high density lipoprotein (HDL). 2. PON1 hydrolyzes organophosphate (OP) insecticides and nerve gases and is responsible for determining the selective toxicity of these compounds in mammals. 3. PON1 has two genetic polymorphisms giving rise to amino acid substitutions at positions 55 and 192. The position-192 polymorphism is the major determinant of the PON1 activity polymorphism. However, the position-55 polymorphism also modulates activity. 4. Genotyping individuals for both PON1 polymorphisms may provide a method for identifying those most at risk of OP poisoning. The effect of the PON1 polymorphisms on activity may explain why some Gulf War veterans have developed Gulf War syndrome and some have not, despite similar OP exposure. 5. PON1 may also be a determinant of resistance to the development of atherosclerosis by protecting lipoproteins against oxidative modification, perhaps by hydrolyzing phospholipid hydroperoxides. 6. The PON 1 polymorphisms are important in determining the capacity of HDL to protect low density lipoprotein against oxidative modification in vitro, which may explain the relation between the PON1 alleles and coronary heart disease in case-control studies.

Arteriosclerosis↗
PubMed1998

Paraoxonase and coronary heart disease.

Paraoxonase (PON1) hydrolyses organophosphate insecticides and nerve gases and is responsible for determining the selective toxicity of these compounds in mammals. Human PON1 has two genetic polymorphisms giving rise to amino-acid substitutions at positions 55 and 192. The 192 polymorphism is the major determinant of the PON1 activity polymorphism towards organophosphates. However, the 55 polymorphism also modulates activity. Ex vivo, the PON1 polymorphisms are important in determining the capacity of HDL to protect LDL against oxidative modification in vitro and this may explain the relationship between the PON1 alleles and coronary heart disease in case-control studies. In recent case-control studies serum PON1 concentration and activity were also found to be decreased in coronary heart disease (CHD) independent of the PON1 polymorphism, and in diabetes serum PON1 specific activity decrease is also independent of the PON1 genetic polymorphism. HDL from transgenic mice lacking PON1 fails to protect LDL against oxidative modification. Thus PON1 may be a determinant of resistance to the development of atherosclerosis by protecting lipoproteins against oxidative modification, perhaps by hydrolysing phospholipid and cholesteryl-ester hydroperoxides.

Animals↗
PubMed1997

Presence of paraoxonase in human interstitial fluid.

Human serum paraoxonase (PON1) is postulated to have anti-atherosclerotic properties through its ability to prevent lipid peroxide generation on LDL. However, in order to perform this role it must be present in interstitial fluid, to prevent LDL oxidation which takes place in the sub-intimal space of the artery wall. The PON1 activity in interstitial fluid was 15.7 (2.3-183.0) (median (range)) nmol/min/ml compared to 105.3 (74.6-323.9) nmol/min/ml in serum. The PON1 concentration in interstitial fluid was found to be 20.2 (1.1-78.1) microg/ml (median (range)) compared to 109.6 (11.1-485.7) microg/ml in serum. Interstitial fluid PON1 concentration was dependent on the interstitial fluid apo AI concentration (r = 0.690, P < 0.005) indicating PON1 remained associated with HDL. However, the ratio of PON1 concentration to apo AI was lower in interstitial fluid (0.60 +/- 0.20) than in the serum (0.95 +/- 0.18) (P < 0.001) indicating sequestration of PON1 in the sub-intimal space. Therefore, PON1 is present and active in interstitial fluid where it can perform its anti-atherosclerotic function.

Adult↗
PubMed1997

Effect of the molecular polymorphisms of human paraoxonase (PON1) on the rate of hydrolysis of paraoxon.

1. The hydrolysis of organophosphate pesticides (OP) and nerve gases by serum paraoxonase (PON1) is an important factor determining their toxicity to mammals including man. The PON1 gene contains 2 polymorphic sites at amino acid positions 55 (L-->M) and 192 (G-->A, classically defined as the A and B genotypes) which result in several alloenzymes of PON1 in human serum. 2. The 192 polymorphism has previously been shown to affect PON1 activity. We have investigated the effect of both polymorphisms on the hydrolysis of paraoxon by serum from 279 healthy human subjects. 3. The 55 polymorphism significantly influenced PON1 activity. MM homozygotes had over 50% less activity towards paraoxon compared to the LL and LM genotypes regardless of the 192 genotype (P < 0.001). 4. Multiple regression analysis indicated that the 192 polymorphism, 55 polymorphism and serum PON1 concentration were responsible for 46, 16 and 13% of the variation in PON1 activity, respectively (all P < 0.001). None of the other parameters investigated significantly affected PON1 activity. 5. Therefore both PON1 polymorphisms affect the hydrolysis of paraoxon. AA/MM and AB/MM individuals may be potentially more susceptible to OP intoxication. 6. Genotyping individuals for both PON1 polymorphisms may provide a method for identifying those individuals at most risk of OP poisoning. The effect of PON1 polymorphisms on activity may also explain why some Gulf War Veterans have developed Gulf War Syndrome and some have not.

Adult↗
PubMed1997

Increased immunolocalization of paraoxonase, clusterin, and apolipoprotein A-I in the human artery wall with the progression of atherosclerosis.

Using immunolocalization techniques, we have shown that paraoxonase (Pon), clusterin, and apolipoprotein (apo) A-I accumulate in the artery wall during the development of atherosclerosis. In normal aortas (n = 6) there were low levels of extracellular Pon, clusterin, and apoA-I, immunoreactivity. The cytoplasm of smooth muscle cells in the media showed granular positivity for both Pon and apoA-I, indicating that these proteins were undergoing lysosomal degradation. This activity was also indicated by the presence of both intact and degradation products of Pon in smooth muscle cells as shown by Western blotting. With the progression of disease from fatty streaks (n = 3) to advanced atherosclerosis (n = 8) there was an increase in Pon, apoA-I, and clusterin immunoreactivity, indicating the increasing presence of these proteins with disease progression. These proteins are the components of a specific HDL subspecies that has been implicated in the prevention of peroxidative damage to phospholipids in LDL and membranes. The increase in Pon, clusterin, and apoA-I during the development of atherosclerosis may therefore represent a protective response to the oxidative stress associated with the development of atherosclerosis.

Adult↗
PubMed1996

Paraoxonase: biochemistry, genetics and relationship to plasma lipoproteins.

Human serum paraoxonase is located on an HDL. It has the capacity to retard the accumulation of lipid peroxides in LDL under oxidizing conditions in vitro. Paraoxonase has a genetic polymorphism that results in a single amino acid substitution. Evidence indicates that both the serum concentration of paraoxonase and an individual's genotype are related to plasma lipid and lipoprotein concentrations, and possibly also to coronary heart disease, implicating paraoxonase in the development of atherosclerosis.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMedDate not supplied

Cuban doctors.

Explore the source record for details and available documents.

Africa, Southern↗