1: Biofactors. 1997;6(3):321-38.

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

Han D, Handelman G, Marcocci L, Sen CK, Roy S, Kobuchi H, Tritschler HJ, Flohé L,
Packer L.

Department of Molecular and Cell Biology, University of California, Berkeley
94720-3200, USA.

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 xc- transport system, which is weakly expressed in
lymphocytes and inhibited by glutamate. Thereby lipoic acid enables the key
enzyme of glutathione synthesis, gamma-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.

PMID: 9288403 [PubMed - indexed for MEDLINE]