In the cystathionine beta-synthase knockout mouse, elevations in total plasma homocysteine increase tissue S-adenosylhomocysteine, but responses of S-adenosylmethionine and DNA methylation are tissue specific.
The cystathionine beta-synthase knockout mouse provides a unique opportunity to study biochemical consequences of a defective cystathionine beta-synthase enzyme. The present study was undertaken to assess the effect of elevated plasma total homocysteine caused by cystathionine beta-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 micro mol/L) was markedly higher than in wild-type mice (7.4 +/- 2.9 micro mol/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 beta-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.
Choumenkovitch
Silvina F
SF
Vitamin Metabolism Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA.
Selhub
Jacob
J
Bagley
Pamela J
PJ
Maeda
Nobuyo
N
Nadeau
Marie R
MR
Smith
Donald E
DE
Choi
Sang-Woon
SW
D000818:Animals; D001483:Base Sequence; D003541:Cystathionine beta-Synthase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D019175:DNA Methylation; D017931:DNA Primers; D005838:Genotype; D006710:Homocysteine / Q000097:blood*; D051379:Mice; D018345:Mice, Knockout; D012435:S-Adenosylhomocysteine / Q000378:metabolism*; D012436:S-Adenosylmethionine / Q000378:metabolism*
D017931:DNA Primers; D006710:Homocysteine; D012436:S-Adenosylmethionine; D004247:DNA; D012435:S-Adenosylhomocysteine; D003541:Cystathionine beta-Synthase