Bucillamine induces glutathione biosynthesis via activation of the transcription factor Nrf2
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Date
2006
Journal Title
Journal ISSN
Volume Title
Publisher
PERGAMON-ELSEVIER SCIENCE LTD
Abstract
The properties of bucillamine, a synthetic antioxidant, have been attributed mainly to the donation of thiol groups to glutathione (GSH). We recently demonstrated that glutamatecysteine ligase catalytic subunit (GCLC), the rate-limiting enzyme of GSH biosynthesis, and the multidrug-resistance-associated protein 2 (Mrp2/MRP2) are coordinately induced in response to xenobiotic through the activation of the antioxidant-response element (ARE) by nuclear factor-erythroid 2 p45-related factor (Nrf2). We tested the hypothesis that bucillamine and its oxidized metabolite SA 981 also activate the Nrf2 pathway, thereby increasing glutathione biosynthesis in human HepG2 and murine Hepa 1-6 hepatoma cell lines, through the induction of the GCLC enzyme as well as the Mrp2/MRP2 transporter, which mediates the excretion of glutathione and its conjugates from hepatocytes. Both bucillamine and SA 981 produced a significant dose-dependent increase in the mRNA levels of Mrp2/MRP2 and GCLC after 24 h. The levels of the transcription factor Nrf2 in the nuclei were maximal at 3 h, remained elevated at 6 h, and decreased to control values at 24 h in both cell lines. Moreover, both bucillamine and SA 981 significantly increased the expressions of Mrp2/MRP2 and GCLC proteins in both cell lines. Finally, in both cell lines, bucillamine and SA 981 increased the GSH content two- to three-fold. These results demonstrate that bucillamine and SA 981 activate the ARE-ARE pathway increasing the expression of ARE-driven genes such as those of GCLC and Mrp2/MRP2. The role of bucillamine as a chemopreventive agent against cancer remains to be elucidated. (c) 2006 Elsevier Inc. All rights reserved.
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Keywords
bucillamine, glutamate-cysteine ligase (GCL), multidrug-resistance associated protein 2(Mrp2/MRP2), glutathione (GSH), nuclear factor-erythroid 2 p45-related factor (Nrf2), GAMMA-GLUTAMYLCYSTEINE SYNTHETASE, GENE-EXPRESSION, INDUCIBLE EXPRESSION, CHEMOPREVENTIVE COMPOUNDS, REPERFUSION INJURY, SUBUNIT GENE, ANTIOXIDANT, INDUCTION, DRUG, MICE