title: 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.
authors.affiliation: Department of Microbiology and Molecular Genetics, UMDNJ-New Jersey Medical School, International Center for Public Health, Newark, NJ 07101, USA.
authors.forename: Kamila
authors.initials: K
authors.lastname: Borowczyk
authors.forename: Diana M
authors.initials: DM
authors.lastname: Shih
authors.forename: Hieronim
authors.initials: H
authors.lastname: Jakubowski
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D043303:Aryldialkylphosphatase / Q000235:genetics* / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D004827:Epilepsy / Q000378:metabolism; D006710:Homocysteine / Q000031:analogs & derivatives* / Q000097:blood / Q000633:toxicity / Q000652:urine; D020138:Hyperhomocysteinemia / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism; D013154:Spleen / Q000378:metabolism
chemical_list: D006710:Homocysteine; C007957:homocysteine thiolactone; D043303:Aryldialkylphosphatase; C560867:PON1 protein, mouse