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Mutations in methylenetetrahydrofolate reductase or cystathionine β‐syntase gene, or a high‐methionine diet, increase homocysteine thiolactone levels in humans and mice
Author(s) -
Chwatko Grazyna,
Boers Godfried H. J.,
Strauss Kevin A.,
Shih Diana M.,
Jakubowski Hieronim
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.06-7435com
Subject(s) - hyperhomocysteinemia , cystathionine beta synthase , homocysteine , methionine , methylenetetrahydrofolate reductase , medicine , endocrinology , methionine synthase , biology , homocystinuria , thiolactone , biochemistry , chemistry , gene , amino acid , genotype , organic chemistry
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 pathophysiolog‐ical pathway that has been implicated in human vascular disease. However, whether genetic deficiencies in Hcy metabolism or a high‐methionine diet affect Hcy‐thio‐lactone levels in mammals has been unknown. Here we show that plasma Hcy‐thiolactone is elevated 59‐fold and 72‐fold in human patients with hyperhomocysteine‐mia secondary to mutations in methylenetetrahydrofo‐late reductase and cystathionine β‐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 (~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 hyperhomocys‐teinemia leads to significant increases in the atherogenic metabolite Hcy‐thiolactone in humans and mice.—Chwatko, G., Boers, G. H. J., Strauss, K. A., Shih, D. M., Jakubowski, H. Mutations in methylenetetrahydrofolate reductase or cystathionine β‐syntase gene, or a high‐methionine diet, increase homocysteine thiolactone levels in humans and mice. FASEB J. 21, 1707–1713 (2007)