Lipoic acid increases de novo synthesis of cellular glutathione by improving cystine utilization

Derick Han, Garry Handelman, Lucia Marcocci, Chandan K. Sen, Sashwati Roy, Hirotsugu Kobuchi, Hans J. Tritschler, Leopold Flohé, Lester Packer

Research output: Contribution to journalArticlepeer-review

313 Citations (Scopus)


Lipoic acid (thiotic acid) is being used as a dietary supplement, and as a therapeutic agent, and is reported to have beneficial effects in disorders associated with oxidative stress, but its mechanism of action remains unclear. We present evidence that lipoic acid induces a substantial increase in cellular reduced glutathione in cultured human Jurkat T cells, human erythrocytes, C6 glial cells, NB41A3 neuroblastoma cells, and peripheral blood lymphocytes. The effect depends on metabolic reduction of lipoic acid to dihydrolipoic acid. Dihydrolipoic acid is released into the culture medium where it reduces cystine. Cysteine thus formed is readily taken up by the neutral amino acid transport system and utilized for glutathione synthesis. By this mechanism lipoic acid enables cystine to bypass the x(c)- transport system, which is weakly expressed in lymphocytes and inhibited by glutamate. Thereby lipoic acid enables the key enzyme of glutathione synthesis, γ-glutamylcysteine synthetase, which is regulated by uptake-limited cysteine supply, to work at optimum conditions. Flow cytometric analysis of freshly prepared human peripheral blood lymphocytes, using monobromobimane labeling of cellular thiols, reveals that lipoic acid acts mainly to normalize a subpopulation of cells severely compromised in thiol status rather then to increase thiol content beyond physiological levels. Hence lipoic acid may have clinical relevance in restoration of severely glutathione deficient cells.

Original languageEnglish
Pages (from-to)321-338
Number of pages18
Issue number3
Publication statusPublished - 1997
Externally publishedYes


  • ASC transporter
  • Cysteine uptake
  • Jurkat cells
  • Peripheral blood lymphocytes
  • Thiols
  • x(c) transporter

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Clinical Biochemistry


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