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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #163472
Title: IN THE CYSTATHIONINE BETA-SYNTHASE KNOCKOUT MOUSE, ELEVATIONS IN TOTAL PLASMA HOMOCYSTENIE INCREASE TISSUE-S-ADENSYLHOMOCYSTEINE, BUT RESPONSES OF S-ADENOSYLMETHIONINE AND DNA METHYLATION ARE TISSUE SPECIFIC

Author
item CHOUMENKOVICH, SILVINA - TUFTS-HNRCA
item SELHUB, JACOB - TUFTS-HNRCA
item BAGLEY, PAMELA - TUFTS-HNRCA
item MAEDA, NOBUYO - UNIV OF NORTH CAROLINA
item NADEAU, MARIE - TUFTS-HNRCA
item SMITH, DONALD - TUFTS-HNRCA
item CHOI, SANG - TUFTS-HNRCA

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/20/2002
Publication Date: 8/1/2002
Citation: CHOUMENKOVICH, S.F., SELHUB, J., BAGLEY, P.J., MAEDA, N., NADEAU, M.R., SMITH, D.E., CHOI, S.W. IN THE CYSTATHIONINE BETA-SYNTHASE KNOCKOUT MOUSE, ELEVATIONS IN TOTAL PLASMA HOMOCYSTENIE INCREASE TISSUE-S-ADENSYLHOMOCYSTEINE, BUT RESPONSES OF S-ADENOSYLMETHIONINE AND DNA METHYLATION ARE TISSUE SPECIFIC. JOURNAL OF NUTRITION. 2002;132(8):2157-60.

Interpretive Summary: Biological methylation is a process which involves the transfer a chemical (methyl) group to S-adenosylmethylation (SAM), to many substances in the body. These methylations serve important functions such as the methylation of DNA in specific gene sites. This methylation serves for the most part, to silence the gene from expression. In this study we determined how DNA methylation is regulated in the various organs. We used mice that produced a lot of homocysteine to form S-adenosylhomocysteine (SAH), which blocks methylation. We found that methylation is blocked in the liver and to some extent in the kidney but not in the brain. These findings emphasizes the capacity of the brain to protect itself in spite of unfavorable environments.

Technical Abstract: 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 was markedly higher than in wild-type mice(P<0.001). In liver only, S-adenosylmethionine concentrations were higher in the homozygous mutant mice than in wild type mice(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 and tended to be lower in kidneybut did not differ in brain. 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.