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

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 PON1 hydrolyzes Hcy-thiolactone in humans and that the interindividual variations in PON1 genotype/activity can modulate the pathology of hyperhomocysteinemia.-Perła-Kaján, J., Borowczyk, K., Głowacki, R., Nygård, O., Jakubowski, H. Paraoxonase 1 Q192r genotype and activity affect homocysteine thiolactone levels in humans.

Urinary excretion of homocysteine thiolactone and the risk of acute myocardial infarction in coronary artery disease patients: the WENBIT trial

“…1) include methionyl-tRNA synthetase (MARS), responsible for the synthesis of Hcy-thiolactone [9,10] and HTases such as PON1, BLMH and BPHL [45][46][47][48], which are responsible for Hcy-thiolactone hydrolysis. Indeed, recent studies found that PON1 Q192R genotype and activity affect Hcy-thiolactone levels in humans [49] and that among CAD patients undergoing percutaneous coronary intervention those with low serum HTase activity show significantly higher all-cause mortality than patients with high HTase activity [50].…”

The Contribution of Homocysteine Metabolism Disruption to Endothelial Dysfunction: State-of-the-Art

“…Interestingly, in the same study, a frequent polymorphism in PON2 , encoding a cellular antioxidant enzyme of the paraoxonase family that protects cells against oxidative stress, was associated with accumulation of HTL [149]. Similarly, a frequent polymorphism in PON1 , which encodes a cardio-protective enzyme known to hydrolyze HTL in vitro, was shown to elicit elevation of urinary HTL levels [150]. Homocysteine thiolactonase activity was also negatively associated with the thickness of the carotid intima media in patients with type 2 diabetes mellitus [151].…”

Homocysteine: Its Possible Emerging Role in At-Risk Population Groups

“…This increasingly prominent protein modification, called N-homocysteinylation, seems to exert cytotoxic, pro-inflammatory, prothrombotic, and pro-atherogenic properties, contributing to the cardiovascular and neurologic disorders of hyperhomocysteinemia (HHcy) [17,18]. Perła-Kaján et al [19] demonstrated that Hcy-thiolactone-hydrolyzing enzymes, known as the paraoxonase (PON) multigene family, associated in the bloodstream with high-density lipoproteinis (PON1/HDL) detoxify homocysteine thiolactone. Therefore, genetic variation in PON1 could compromise this activity in humans.…”