Metabolism and Neurotoxicity of Homocysteine Thiolactone in Mice: Evidence for a Protective Role of Paraoxonase 1

Abstract

Homocysteine (Hcy)-thiolactone is toxic, induces epileptic seizures in rodents, and has been implicated in Alzheimer’s disease. Paraoxonase 1 (Pon1), a component of high-density lipoprotein, hydrolyzes Hcy-thiolactone in vitro. Whether this reflects a physiological function and whether Pon1 can protect against Hcy-thiolactone toxicity was unknown. Here we show that Hcy-thiolactone was elevated in brains of Pon1−/− mice (1.5-fold, p = 0.047) and that Pon1−/− mice excrete more Hcy-thiolactone than wild type animals (2.4-fold, p = 0.047). The frequency of seizures induced by intraperitoneal injections of L-Hcy-thiolactone was significantly higher in Pon1−/− mice compared with wild type animals (52.8% versus 29.5%, p = 0.042); the latency of seizures was lower in Pon1−/− mice than in wild type animals (31.8 min versus 41.2 min, p = 0.019). Using the Pon1 null mice, we provide the first direct evidence that a specific Hcy metabolite, Hcy-thiolactone, rather than Hcy itself is neurotoxic in vivo. Our findings indicate that Pon1 protects mice against Hcy-thiolactone neurotoxicity by hydrolyzing it in the brain, and suggest a mechanism by which Pon1 can protect against neurodegeneration associated with hyperhomocysteinemia and Alzheimer’s disease.

Multiple Cytochrome P450 Isoforms Are Involved in the Generation of a Pharmacologically Active Thiol Metabolite, whereas Paraoxonase 1 and Carboxylesterase 1 Catalyze the Formation of a Thiol Metabolite Isomer from Ticlopidine

“…These results collectively indicated that PON1 was primarily involved in M1 formation from 2-oxo-ticlopidine. PON1 is known to be involved in the hydrolysis of lactone or thiolactone derivatives such as pilocarpine (Billecke et al, 2000;Hioki et al, 2011) and homocysteine thiolactone (Borowczyk et al, 2012).…”

Paraoxonase 1 deficiency and hyperhomocysteinemia alter the expression of mouse kidney proteins involved in renal disease

“…Reduced PON1 activity is linked to cardiovascular disease [7,8]. In mice, Pon1 gene deletion impairs urine concentrating ability, which leads to a polyuria phenotype [9].…”

“…Hcy is a negative determinant of HDL and PON1 [17] and reduces Apoa1 and Pon1 gene expression [18]. HDL and purified PON1 detoxify Hcy-thiolactone [19] and protect against protein Nhomocysteinylation [9,20]. N-Homocysteinylation causes protein damage and is linked to kidney and cardiovascular diseases (reviewed in [21]).…”

Paraoxonase 1 in neurological disorders

“…It is a homocysteine-thiolactonase. [31][32][33][34] PON1 evolved from bi-functional enzymes that act as homoserine lactones which are quorum-sensing molecules employed by many gram-negative bacteria. PON1 is thereby a component of the innate immunity.…”