Department of Medicine and Division of Hematology, University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045, USA.
Free Radic Biol Med. 2009 Oct 15;47(8):1147-53. doi: 10.1016/j.freeradbiomed.2009.07.019. Epub 2009 Jul 17.
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.
硫辛酸是一种含二硫键的化合物，在临床医学和实验模型中被用作抗氧化剂。我们开发了一种稳定同位素稀释毛细管气相色谱/质谱法测定硫辛酸的方法。我们在大鼠模型中注射 100mg/kg 硫辛酸 30 分钟后，检测了转甲基和转硫过程中一组代谢物。硫辛酸在血清中的浓度升高了 1000 倍，在肝脏中的浓度升高了 10 倍。还检测到但未定量的硫辛酸的甲基化代谢物。硫辛酸注射导致血清 S-腺苷同型半胱氨酸大量增加，肝脏 S-腺苷甲硫氨酸明显耗竭。血清总半胱氨酸耗竭，但肝脏半胱氨酸和谷胱甘肽得以维持。血清总同型半胱氨酸增加了一倍，胱硫醚、N,N-二甲基甘氨酸和α-氨基丁酸也增加了。相比之下，注射 2-巯基乙烷磺酸后，血清总半胱氨酸和同型半胱氨酸明显耗竭，对血清 S-腺苷甲硫氨酸或 S-腺苷同型半胱氨酸没有影响。我们的结论是，大剂量的硫辛酸从结合位点取代巯基，导致血清半胱氨酸耗竭，但也会造成甲基化负担，导致肝脏 S-腺苷甲硫氨酸严重耗竭和 S-腺苷同型半胱氨酸大量释放。这些变化可能具有以前未被认识到的有害影响，应在人类疾病和实验模型中进行研究。
