Paraoxonase 1 (PON1) attenuates diabetes development in mice through its antioxidative properties

Rozenberg, Orit; Shiner, Maayan; Aviram, Michael; Hayek, Tony

doi:10.1016/j.freeradbiomed.2008.02.012

Cited by 67 publications

(41 citation statements)

References 68 publications

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“…The significant association between PON1 L55M carriage and diabetes is of importance given the established correlation between PON1 activity and the occurrence of diabetes, 25,26 glucose intolerance, 27 and vascular complications in diabetics. 28 Moreover, PON1 genetic polymorphisms have also been associated with an overall increase in cardiovascular risk.…”

Section: Discussionmentioning

confidence: 99%

CYP2C19 But Not PON1 Genetic Variants Influence Clopidogrel Pharmacokinetics, Pharmacodynamics, and Clinical Efficacy in Post–Myocardial Infarction Patients

Hulot

Collet

Cayla

et al. 2011

Circ: Cardiovascular Interventions

109

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Background-Reduced concentrations of clopidogrel active metabolite have been associated with diminished platelet inhibition and higher rates of adverse cardiovascular events. Paraoxonase-1 (PON1) has recently been proposed as a key enzyme for clopidogrel metabolic activation. We tested the effects of PON1 polymorphisms on clopidogrel pharmacokinetics and pharmacodynamics and the occurrence of cardiovascular outcomes in young post-myocardial infarction (MI) patients treated with clopidogrel. Methods and Results-We genotyped PON1 (Q192R and L55M) and CYP2C19 variants in 106 patients enrolled in the PK/PD CLOVIS-2 trial. Patients were randomly exposed to a 300-mg or 900-mg clopidogrel loading dose in a crossover study design. Clopidogrel active metabolite isomer H4 (clopi-H4) and platelet function testing were measured serially after loading dose. There was no significant association between PON1 Q192R or L55M and clopi-H4 formation or antiplatelet response to clopidogrel after either loading dose. Using multivariable linear regression analyses, the CYP2C19*2 allele was the only predictor of clopi-H4 generation and platelet response irrespective of the platelet function assay. CYP2C19 loss-of-function but not PON1 variants were significantly associated with increased risk of major cardiovascular events (death, MI, and urgent coronary revascularization) occurring during long-term clopidogrel exposure in 371 young post-MI patients (age Ͻ45 years) enrolled in the AFIJI cohort (CYP2C19

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Section: Discussionmentioning

confidence: 99%

CYP2C19 But Not PON1 Genetic Variants Influence Clopidogrel Pharmacokinetics, Pharmacodynamics, and Clinical Efficacy in Post–Myocardial Infarction Patients

Hulot

Collet

Cayla

et al. 2011

Circ: Cardiovascular Interventions

109

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“…Recently it has been shown that human PON1 can prevent diabetes development in mice through its antioxidant properties and the stimulation of beta-cell insulin release, suggesting a possible role for PON1 in insulin biosynthesis [37,38]. PON2 also has an important role in hepatic insulin signalling [39] which may suggest a role for the PON family in energy metabolism which requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

Paraoxonase-1 Is Not Associated with Coronary Artery Calcification in Type 2 Diabetes: Results from the PREDICT Study

Mackness¹,

Marsillach

Elkeles

et al. 2012

Disease Markers

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Abstract. Objectives:To determine any association between serum paraoxonase-1 (PON1) activity, protein and coding region genetic polymorphisms and coronary artery calcification (CACS) and to determine factors which modulate serum PON1 in type 2 diabetes (T2DM). Methods and results: 589 patients (419 Caucasian, 120 South Asian, 50 other) from the PREDICT Study were investigated. All patients were asymptomatic for coronary disease and had established T2DM. CACS, lipids, lipoproteins, inflammatory markers, insulin resistance and PON1 activity, concentration and Q192R and L55M genotypes were measured. Independent associations were: 1) PON1 activity negatively with insulin resistance, triglycerides and PON1-55 genotype and positively with PON1-192 genotype; 2) PON1 concentration negatively with Caucasian ethnicity, duration of diabetes and statin use and positively with plasma creatinine and PON1-192 genotype. There was no association between CACS and any of the PON1 activity, concentration or genotype and this finding was not different in the various ethnic groups within the PREDICT study. Conclusion: PON1 is modulated by a number of factors, some of which are reported here for the first time, including ethnicity and insulin resistance in subjects with T2DM. No association between CACS and PON1 was found.

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“…PON1-overexpressing mice had decreased diabetesinduced macrophage oxidative stress, decreased risk of development of diabetes, and decreased mortality compared with wild-type mice; this phenotype was even more dramatic when compared with that of PON1 knockout mice. PON1 was therefore hypothesized to be able to attenuate the development of diabetes because of its antioxidative properties (287). Low PON1 activity is also related to higher CRP, which is independent of adipokines, obesity, and lipids.…”

Section: A Pons' Relations To Diabetes Mellitus and Corresponding Comentioning

confidence: 99%

The Human Paraoxonase Gene Cluster As a Target in the Treatment of Atherosclerosis

She

Chen

Yan

et al. 2012

Antioxidants & Redox Signaling

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The paraoxonase (PON) gene cluster contains three adjacent gene members, PON1, PON2, and PON3. Originating from the same fungus lactonase precursor, all of the three PON genes share high sequence identity and a similar b propeller protein structure. PON1 and PON3 are primarily expressed in the liver and secreted into the serum upon expression, whereas PON2 is ubiquitously expressed and remains inside the cell. Each PON member has high catalytic activity toward corresponding artificial organophosphate, and all exhibit activities to lactones. Therefore, all three members of the family are regarded as lactonases. Under physiological conditions, they act to degrade metabolites of polyunsaturated fatty acids and homocysteine (Hcy) thiolactone, among other compounds. By detoxifying both oxidized low-density lipoprotein and Hcy thiolactone, PONs protect against atherosclerosis and coronary artery diseases, as has been illustrated by many types of in vitro and in vivo experimental evidence. Clinical observations focusing on gene polymorphisms also indicate that PON1, PON2, and PON3 are protective against coronary artery disease. Many other conditions, such as diabetes, metabolic syndrome, and aging, have been shown to relate to PONs. The abundance and/or activity of PONs can be regulated by lipoproteins and their metabolites, biological macromolecules, pharmacological treatments, dietary factors, and lifestyle. In conclusion, both previous results and ongoing studies provide evidence, making the PON cluster a prospective target for the treatment of atherosclerosis. Antioxid. Redox Signal. 16, 597-632.

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Paraoxonase 1 (PON1) attenuates diabetes development in mice through its antioxidative properties

Cited by 67 publications

References 68 publications

CYP2C19 But Not PON1 Genetic Variants Influence Clopidogrel Pharmacokinetics, Pharmacodynamics, and Clinical Efficacy in Post–Myocardial Infarction Patients

CYP2C19 But Not PON1 Genetic Variants Influence Clopidogrel Pharmacokinetics, Pharmacodynamics, and Clinical Efficacy in Post–Myocardial Infarction Patients

Paraoxonase-1 Is Not Associated with Coronary Artery Calcification in Type 2 Diabetes: Results from the PREDICT Study

The Human Paraoxonase Gene Cluster As a Target in the Treatment of Atherosclerosis

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