Resveratrol increases gamma-glutamylcysteine synthetase subunit mRNAs
Tim
Erratum in:
Free Radic Biol Med 2002 Jul 31;33(1):149. Guis David [corrected to
Gius David]
Redox-sensitive interaction between KIAA0132 and Nrf2 mediates
indomethacin-induced expression of gamma-glutamylcysteine synthetase.
It appears that resveratrol may be acting at least in part, via Nrf2
activation of the ARE which phenolic antioxidants like BHT and
curcumin do as well (though not stated). This paper only notes that
the anti-inflammatory indomethacin does the same but it's effects are
nullified by NAC. Whether taking lipoic acid and NAC with resveratrol
nullifies it's effect is unknown to me. (Nrf2 can be activated
apparently in a number of ways which effects the genes they
induce)However, the effects of curcumin on Nrf2 mediated ARE genes has
been found to not be nullified by co-administration of NAC. So it may
well be that they work better together.
Sekhar KR, Spitz DR, Harris S, Nguyen TT, Meredith MJ, Holt JT, Gius
D, Marnett LJ, Summar ML, Freeman ML, Guis D.
Dept of Radiation Oncology, Vanderbilt University School of Medicine,
Nashville, TN 37232, USA.
Exposure of HepG2 cells to nonsteroidal anti-inflammatory drugs (i.e.,
indomethacin and ibuprofen; NSAIDs) as well as resveratrol, caused
increased expression of the mRNAs coding for the catalytic (Gclc) and
modifier (Gclm) subunits of the glutathione synthetic enzyme,
gamma-glutamylcysteine synthetase. In addition, indomethacin exposure
increased intracellular glutathione content as well as inhibited
glutathione depletion and cytotoxicity caused by diethyl maleate.
Indomethacin-induced increases in the expression of
gamma-glutamylcysteine synthetase mRNA were preceded by increases in
steady state levels of intracellular pro-oxidants and glutathione
disulfide accumulation. Simultaneous incubation with the thiol
antioxidant N-acetylcysteine (NAC) inhibited indomethacin-mediated
increases in GCLC mRNA, suggesting that increases in GCLC message were
triggered by changes in intracellular oxidation/reduction (redox)
reactions. Indirect immunofluorescence using intact cells demonstrated
that indomethacin induced the nuclear translocation of Nrf2, a
transcription factor believed to regulate GCLC expression.
Immunoprecipitation studies showed that indomethacin treatment also
inhibited Nrf2 tethering to KIAA0132 (the human homolog of Keap1
accession #D50922), which is believed to be a negative regulator of
Nrf2. Consistent with this idea, over-expression of Nrf2 increased
GCLC reporter gene expression and over-expression of KIAA0132
inhibited GCLC reporter gene activity as well as inhibited
indomethacin-induced increases in the expression of GCLC. Finally,
simultaneous treatment with NAC inhibited both indomethacin-induced
release of Nrf2 from KIAA0132 and indomethacin-induced nuclear
translocation of Nrf2. These results demonstrate that NSAIDs and
resveratrol cause increases in the expression of
gamma-glutamylcysteine synthetase mRNA and identify these agents as
being capable of stimulating glutathione metabolism. These results
also support the hypothesis that indomethacin-induced transcriptional
activation of GCLC involves the redox-dependent release of KIAA0132
from Nrf2 followed by the nuclear translocation of Nrf2.
PMID: 11909699 [PubMed - indexed for MEDLINE]
Tim