title: Elevation in S-adenosylhomocysteine and DNA hypomethylation: potential epigenetic mechanism for homocysteine-related pathology.
abstract: Chronic nutritional deficiencies in folate, choline, methionine, vitamin B-6 and/or vitamin B-12 can perturb the complex regulatory network that maintains normal one-carbon metabolism and homocysteine homeostasis. Genetic polymorphisms in these pathways can act synergistically with nutritional deficiencies to accelerate metabolic pathology associated with occlusive heart disease, birth defects and dementia. A major unanswered question is whether homocysteine is causally involved in disease pathogenesis or whether homocysteinemia is simply a passive and indirect indicator of a more complex mechanism. S-Adenosylmethionine and S-adenosylhomocysteine (SAH), as the substrate and product of methyltransferase reactions, are important metabolic indicators of cellular methylation status. Chronic elevation in homocysteine levels results in parallel increases in intracellular SAH and potent product inhibition of DNA methyltransferases. SAH-mediated DNA hypomethylation and associated alterations in gene expression and chromatin structure may provide new hypotheses for pathogenesis of diseases related to homocysteinemia.
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA. jjames@nctr.fda.gov
authors.forename: S Jill
authors.initials: SJ
authors.lastname: James
authors.forename: Stepan
authors.initials: S
authors.lastname: Melnyk
authors.forename: Marta
authors.initials: M
authors.lastname: Pogribna
authors.forename: Igor P
authors.initials: IP
authors.lastname: Pogribny
authors.forename: Marie A
authors.initials: MA
authors.lastname: Caudill
mesh_terms: D000818:Animals; D002908:Chronic Disease; D019175:DNA Methylation; D006710:Homocysteine / Q000097:blood / Q000502:physiology*; D006801:Humans; D012435:S-Adenosylhomocysteine / Q000378:metabolism*
chemical_list: D006710:Homocysteine; D012435:S-Adenosylhomocysteine