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Mutations in methylenetetrahydrofolate reductase or cystathionine ß-syntase gene, or a high-methionine diet, increase homocysteine thiolactone levels in humans and mice

Grazyna Chwatko^*,1, Godfried H. J. Boers, Kevin A. Strauss, Diana M. Shih and Hieronim Jakubowski^*,||,2

^* Department of Microbiology and Molecular Genetics, UMDNJ-New Jersey Medical School, International Center for Public Health, Newark, New Jersey, USA;

Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands;

Clinic for Special Children, Strasburg, Pennsylvania, USA;

Department of Medicine, UCLA Medical School, Los Angeles, California, USA; and

^|| Institute of Bioorganic Chemistry, Polish Academy of Sciences, Pozna, Poland

²Correspondence: Department of Microbiology and Molecular Genetics, UMDNJ-New Jersey Medical School, International Center for Public Health, 225 Warren St., Newark, NJ 07101-1709, USA. E-mail: jakubows{at}umdnj.edu

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 ß-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 hyperhomocysteinemia 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 ß-syntase gene, or a high-methionine diet, increase homocysteine thiolactone levels in humans and mice.

Key Words: genetic hyperhomocysteinemia • dietary hyperhomocysteinemia • atherosclerosis