title: Alpha-lipoic acid induces elevated S-adenosylhomocysteine and depletes S-adenosylmethionine.
abstract: Lipoic acid is a disulfhydryl-containing compound used in clinical medicine and in experimental models as an antioxidant. We developed a stable isotope dilution capillary gas chromatography/mass spectrometry assay for lipoic acid. We assayed a panel of the metabolites of transmethylation and transsulfuration 30 min after injecting 100 mg/kg lipoic acid in a rat model. Lipoic acid values rose 1000-fold in serum and 10-fold in liver. A methylated metabolite of lipoic acid was also detected but not quantitated. Lipoic acid injection caused a massive increase in serum S-adenosylhomocysteine and marked depletion of liver S-adenosylmethionine. Serum total cysteine was depleted but liver cysteine and glutathione were maintained. Serum total homocysteine doubled, with increases also in cystathionine, N,N-dimethylglycine, and alpha-aminobutyric acid. In contrast, after injection of 2-mercaptoethane sulfonic acid, serum total cysteine and homocysteine were markedly depleted and there were no effects on serum S-adenosylmethionine or S-adenosylhomocysteine. We conclude that large doses of lipoic acid displace sulfhydryls from binding sites, resulting in depletion of serum cysteine, but also pose a methylation burden with severe depletion of liver S-adenosylmethionine and massive release of S-adenosylhomocysteine. These changes may have previously unrecognized deleterious effects that should be investigated in both human disease and experimental models.
authors.affiliation: Department of Medicine and Division of Hematology, University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045, USA. Sally.Stabler@ucdenver.edu
authors.forename: Sally P
authors.initials: SP
authors.lastname: Stabler
authors.forename: Jeevan
authors.initials: J
authors.lastname: Sekhar
authors.forename: Robert H
authors.initials: RH
authors.lastname: Allen
authors.forename: Heidi C
authors.initials: HC
authors.lastname: O'Neill
authors.forename: Carl W
authors.initials: CW
authors.lastname: White
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D003545:Cysteine / Q000097:blood / Q000172:deficiency; D008401:Gas Chromatography-Mass Spectrometry; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008745:Methylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012435:S-Adenosylhomocysteine / Q000378:metabolism*; D012436:S-Adenosylmethionine / Q000378:metabolism*; D008063:Thioctic Acid / Q000097:blood / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D008063:Thioctic Acid; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D003545:Cysteine