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

Genetic disorders of homocysteine(Hcy) metabolism or a high-methionine diet lead toelevations of plasma Hcy levels. In humans, severegenetic hyperhomocysteinemia results in prematuredeath from vascular complications whereas dietaryhyperhomocysteinemia is often used to induce athero-sclerosis in animal models. Hcy is mistakenly selectedin place of methionine by methionyl-tRNA synthetaseduring protein biosynthesis, which results in the forma-tion of Hcy-thiolactone and initiates a pathophysiolog-ical pathway that has been implicated in human vasculardisease. However, whether genetic deficiencies in Hcymetabolism or a high-methionine diet affect Hcy-thio-lactone levels in mammals has been unknown. Here weshow that plasma Hcy-thiolactone is elevated 59-foldand 72-fold in human patients with hyperhomocysteine-mia secondary to mutations in methylenetetrahydrofo-late reductase and cystathionine -synthase genes, re-spectively. We also show that mice, like humans,eliminate Hcy-thiolactone by urinary excretion; in con-trast to humans, however, mice also eliminate signifi-cant amounts of plasma total Hcy (38%) by urinaryexcretion. In mice, hyperhomocysteinemia secondaryto a high-methionine diet leads to 3.7-fold and 25-foldincreases in plasma and urinary Hcy-thiolactone levels,respectively. Thus, we conclude that hyperhomocys-teinemia leads to significant increases in the athero-genic metabolite Hcy-thiolactone in humans and mice.