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Redox Regulation of Glutathione S-Transferase Induction by Benzyl Isothiocyanate: Correlation of Enzyme Induction with the Formation of Reactive Oxygen Intermediates¹

Laboratories of Organic Chemistry in Life Science [Y. N., H. O.] and Biosignals and Response [S. M.], Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502; Department of Biotechnological Science, Faculty of Biology-Oriented Science and Technology, Kinki University, Wakayama 649-6493 [A. M.]; Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, 565-0871 [M. I.]; and Laboratory of Food and Biodynamics, Nagoya University Graduate School of Bioagricultural Sciences, Nagoya 464-8601 [Y. M., Y. K., T. O., K. U.], Japan

Here we report the molecular mechanism underlying the induction of glutathione S-transferase (GST) in rat liver epithelial RL34 cells treated with a cancer chemopreventive isothiocyanate compound, benzylisothiocyanate (BITC). BITC was found to significantly induce GST activity in RL34 cells. Northern and Western blot analyses demonstrated that BITC specifically enhanced the production of the class GST isozyme (GSTP1). Our studies demonstrated for the first time that the addition of BITC to the cells resulted in an immediate increase in the reactive oxygen intermediates (ROIs) detected by a fluorescence probe, 2',7'-dichlorofluorescin diacetate. The level of the ROIs in the cells treated with BITC (10 µM) was 50-fold higher than those in the control cells. Furthermore, glutathione depletion by diethyl maleate significantly enhanced BITC-induced ROI production and accelerated the BITC-induced elevation of the GST activity, whereas pretreatment of the cells with glutathione inhibited both the ROI production and GST induction. The structure-activity relationship of the isothiocyanates also indicated that the ROI-producing activities closely correlated with their GST-inducing potencies. Moreover, the GSTP1 enhancer I-containing region was found to be essential for induction of the GSTP1 gene by intracellular ROI inducers such as BITC and diethyl maleate. These data suggest the involvement of the redox regulation on the induction of GSTP1 by BITC.

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