α-Lipoic acid induces elevated S-adenosylhomocysteine and depletes S-adenosylmethionine

• Published in: Free radical biology & medicine Vol. 47; no. 8; pp. 1147 - 1153
• Main Authors: Stabler, Sally P., Sekhar, Jeevan, Allen, Robert H., O'Neill, Heidi C., White, Carl W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.10.2009
• Subjects: Animals; Antioxidants - pharmacology; Cysteine; Cysteine - blood; Cysteine - deficiency; Free radicals; Gas Chromatography-Mass Spectrometry; Homocysteine; Liver - drug effects; Liver - metabolism; Male; Methionine; Methylation; Rats; Rats, Sprague-Dawley; S-Adenosylhomocysteine - metabolism; S-Adenosylmethionine - metabolism; Thioctic Acid - blood; Thioctic Acid - pharmacology; Transmethylation; Transsulfuration; Cysteine; Free radicals; DTT; ip; Methionine; SAHH; tHcys; MESNA; LA; CBS; BMBA; Transmethylation; DHLA; SAH; BMHA; Homocysteine; Transsulfuration; SAM
• ISSN: 0891-5849; 1873-4596; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2009.07.019

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 α-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.