Paraoxonase 1 Q192R genotype and activity affect homocysteine thiolactone levels in humans

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
Joanna Perła-KajánHieronim Jakubowski

Abstract

Genetic or nutritional deficiencies in 1 carbon and homocysteine (Hcy) metabolism elevate Hcy-thiolactone levels and are associated with cardiovascular and neurologic diseases. Hcy-thiolactone causes protein damage, cellular toxicity, and proatherogenic changes in gene expression in human cells and tissues. A polymorphic cardio-protective enzyme, paraoxonase 1 (PON1), hydrolyzes Hcy-thiolactone in vitro. However, whether Hcy-thiolactone hydrolysis is a physiologic function of the PON1 protein and whether polymorphisms in the PON1 gene affect Hcy-thiolactone levels in humans was unknown. Here we show that the PON1-192 genotype, which affects the enzymatic activity of the PON1 protein, also affected urinary Hcy-thiolactone levels, normalized to creatinine. Carriers of the PON1-192R allele had significantly lower Hcy-thiolactone/creatinine levels than individuals carrying the PON1-192Q allele. Individuals with low serum PON1 paraoxonase activity had significantly higher Hcy-thiolactone/creatinine levels compared with individuals with high paraoxonase activity. In contrast, Hcy-thiolactone/creatinine levels were unaffected by serum PON1 arylesterase activity or by PON1 protein levels. Taken together, these findings suggest that PON...Continue Reading

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Citations

Nov 15, 2018·Physiological Reviews·Hieronim Jakubowski
May 5, 2020·Journal of Internal Medicine·H Jakubowski
Jun 4, 2020·Current Opinion in Lipidology·Abdolkarim Mahrooz, Mike Mackness
Jun 30, 2019·International Journal of Molecular Sciences·Joanna Perła-Kaján, Hieronim Jakubowski
Feb 26, 2020·International Journal of Molecular Sciences·Elena AzziniAngela Polito
Feb 20, 2019·International Journal of Molecular Sciences·Ruben EsseRita Castro
Dec 16, 2020·Expert Review of Proteomics·Hieronim Jakubowski
Apr 6, 2021·Alzheimer's & Dementia : Translational Research & Clinical Interventions·Olga WłoczkowskaHieronim Jakubowski
May 4, 2021·Journal of Alzheimer's Disease : JAD·Joanna Perła-KajánHieronim Jakubowski
Jul 3, 2021·International Journal of Molecular Sciences·Miljana NenkovYuan Chen

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