title: Mutations in methylenetetrahydrofolate reductase or cystathionine beta-synthase gene, or a high-methionine diet, increase homocysteine thiolactone levels in humans and mice.
abstract: Genetic disorders of homocysteine (Hcy) metabolism or a high-methionine diet lead to elevations of plasma Hcy levels. In humans, severe genetic hyperhomocysteinemia results in premature death from vascular complications whereas dietary hyperhomocysteinemia is often used to induce atherosclerosis in animal models. Hcy is mistakenly selected in place of methionine by methionyl-tRNA synthetase during protein biosynthesis, which results in the formation of Hcy-thiolactone and initiates a pathophysiological pathway that has been implicated in human vascular disease. However, whether genetic deficiencies in Hcy metabolism or a high-methionine diet affect Hcy-thiolactone levels in mammals has been unknown. Here we show that plasma Hcy-thiolactone is elevated 59-fold and 72-fold in human patients with hyperhomocysteinemia secondary to mutations in methylenetetrahydrofolate reductase and cystathionine beta-synthase genes, respectively. We also show that mice, like humans, eliminate Hcy-thiolactone by urinary excretion; in contrast to humans, however, mice also eliminate significant amounts of plasma total Hcy (approximately 38%) by urinary excretion. In mice, hyperhomocysteinemia secondary to a high-methionine diet leads to 3.7-fold and 25-fold increases in plasma and urinary Hcy-thiolactone levels, respectively. Thus, we conclude that hyperhomocysteinemia leads to significant increases in the atherogenic metabolite Hcy-thiolactone in humans and mice.
authors.affiliation: Department of Microbiology and Molecular Genetics, UMDNJ-New Jersey Medical School, International Center for Public Health, 225 Warren St., Newark, NJ 07101-1709, USA.
authors.forename: Grazyna
authors.initials: G
authors.lastname: Chwatko
authors.forename: Godfried H J
authors.initials: GH
authors.lastname: Boers
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Strauss
authors.forename: Diana M
authors.initials: DM
authors.lastname: Shih
authors.forename: Hieronim
authors.initials: H
authors.lastname: Jakubowski
mesh_terms: D000818:Animals; D003541:Cystathionine beta-Synthase / Q000235:genetics*; D006710:Homocysteine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000652:urine; D006801:Humans; D020138:Hyperhomocysteinemia / Q000209:etiology; D008715:Methionine / Q000008:administration & dosage*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D051379:Mice; D009154:Mutation
chemical_list: D006710:Homocysteine; D008715:Methionine; C007957:homocysteine thiolactone; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D003541:Cystathionine beta-Synthase