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J. Biol. Chem., Vol. 275, Issue 38, 29318-29323, September 22, 2000
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,,,§
From the S-Adenosylmethionine and
S-adenosylhomocysteine (SAH), as the substrate and product
of essential cellular methyltransferase reactions, are important
metabolic indicators of cellular methylation status. Chronic elevation
of SAH, secondary to the homocysteine-mediated reversal of the SAH
hydrolase reaction, reduces methylation of DNA, RNA, proteins, and
phospholipids. High affinity binding of SAH to the active site of
cellular methyltransferases results in product inhibition of the
enzyme. Using a sensitive new high pressure liquid
chromatography method with coulometric electrochemical detection, plasma SAH levels in healthy young women were found to
increase linearly with mild elevation in homocysteine levels (r = 0.73; p < 0.001); however,
S-adenosylmethionine levels were not affected. Plasma SAH
levels were positively correlated with intracellular lymphocyte SAH
levels (r = 0.81; p < 0.001) and also with lymphocyte DNA hypomethylation (r = 0.74, p < 0.001). These results suggest that chronic
elevation in plasma homocysteine levels, such as those associated
with nutritional deficiencies or genetic polymorphisms in the folate
pathway, may have an indirect and negative effect on cellular
methylation reactions through a concomitant increase in
intracellular SAH levels.
Division of Biochemical Toxicology,
FDA-National Center for Toxicological Research, Jefferson, Arkansas
72079 and the § Department of Biochemistry and Molecular
Biology and the ¶ School of Health-Related Professionals,
University of Arkansas for Medical Sciences,
Little Rock, Arkansas 72202
To whom correspondence should be addressed: National Center
for Toxicological Research, 3900 NCTR Rd., Jefferson, AR 72079. Tel.:
870-543-7306; Fax: 870-543-7720; E-mail:
jjames@nctr.fda.gov.
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