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

• Published in: The FASEB journal 2018-11, Vol.32 (11), p.6019-6024
• Main Authors: Perła-Kajá, n, Joanna, Borowczyk, Kamila, Głowacki, Rafał, Nygård, Ottar, Jakubowski, Hieronim
• Format: Article
• Language: English
• Subjects: BLMH; BPHL; MARS; PON1
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.201800346R

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 lowerHcy‐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 in terindividual variations in PON1 genotype/activity can modulate the pathology of hyperhomocysteinemia.—Perla‐Kaján, J., Borowczyk, K., Glowacki, R., Nygard, O., Jakubowski, H. Paraoxonase 1 Q192R genotype and activity affect homocysteine thiolactone levels in humans. 32, 6019–6024 (2018). www.fasebj.org