In the Cystathionine β-Synthase Knockout Mouse, Elevations in Total Plasma Homocysteine Increase Tissue S-Adenosylhomocysteine, but Responses of S-Adenosylmethionine and DNA Methylation Are Tissue Specific

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Abstract
The cystathionine β-synthase knockout mouse provides a unique opportunity to study biochemical consequences of a defective cystathionine β-synthase enzyme. The present study was undertaken to assess the effect of elevated plasma total homocysteine caused by cystathionine β-synthase deficiency on one-carbon metabolism in 10 homozygous mutant mice and 10 age- and sex-matched wild-type mice. Plasma total homocysteine levels, S-adenosylmethionine and S-adenosylhomocysteine concentrations in liver, kidney and brain were measured by HPLC. Tissue DNA methylation status was measured by in vitro DNA methyl acceptance. Plasma total homocysteine concentration in food-deprived homozygous mutant mice (271.1 ± 61.5 μmol/L) was markedly higher than in wild-type mice (7.4 ± 2.9 μmol/L) (P < 0.001). In liver only, S-adenosylmethionine concentrations were higher in the homozygous mutant mice (35.6 ± 5.9 nmol/g) than in wild type mice (19.1 ± 6.1 nmol/g) (P < 0.001) and tended to be lower in kidney (P = 0.07). In contrast, S-adenosylhomocysteine concentrations were significantly higher in homozygous mutant mice compared with wild-type mice in all tissues studied. Genomic DNA methylation status in homozygous mutant compared with wild-type mice was lower in liver (P = 0.037) and tended to be lower in kidney (P = 0.077) but did not differ in brain (P = 0.46). The results of this study are consistent with the predicted role of cystathionine β-synthase in the regulation of plasma total homocysteine levels and tissue S-adenosylhomocysteine levels. However, the fact that the absence of the enzyme had differential effects on S-adenosylmethionine concentrations and DNA methylation status in different tissues suggests that regulation of biological methylation is a complex tissue-specific phenomenon.