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

Authors

  • Derick Han,

    1. Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720–3200, USA
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  • Garry Handelman,

    1. Antioxidant Research Lab USDA-HNRC, Tufts University, Boston, MA 02111, USA
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  • Lucia Marcocci,

    1. Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720–3200, USA
    2. Department of Biochemical Sciences ‘A. Rossi Fanelli’ and CNR Center for Molecular Biology, University of Rome ‘La Sapienza’, Rome 00185, Italy
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  • Chandan K. Sen,

    1. Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720–3200, USA
    2. Department of Physiology, Faculty of Medicine, University of Kuopio, FIN 70211, Finland
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  • Sashwati Roy,

    1. Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720–3200, USA
    2. Department of Physiology, Faculty of Medicine, University of Kuopio, FIN 70211, Finland
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  • Hirotsugu Kobuchi,

    1. Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720–3200, USA
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  • Hans J. Tritschler,

    1. ASTA Medica AG, Weismüllerstraβe, 45, D-60314 Frankfurt Am Main, Germany
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  • Leopold Flohé,

    1. Department of Physiological Chemistry, Technical University of Braunschweig, D-38124 Braunschweig, Germany
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  • Lester Packer

    Corresponding author
    1. Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720–3200, USA
    • University of California, Department of Molecular and Cell Biology, 251 Life Sciences Addition, Berkeley, CA 94720–3200, USA. Tel.: +1 510 642 1872; Fax: +1 510 642 8313
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Abstract

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 χ-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 than to increase thiol content beyond physiological levels. Hence lipoic acid may have clinical relevance in restoration of severely glutathione deficient cells.

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