Regulation of phase 2 enzyme response by dithiolethiones: Oltipraz as a paradigm

Abstract

Oltipraz (OPZ), a member of a class of 1,2-dithiolethiones is a potent phase 2 enzyme inducing agent used as a cancer chemopreventive. In this study we investigated regulation of the phase 2 enzyme response and protection against endogenous oxidative stress in lymphoblastic leukemic CEM cells lacking mitochondrial DNA (mtDNA) (r0) by OPZ. Reduced GSH levels (total and mitochondrial) and GST activity were significantly increased after pretreatment with OPZ in both parental (r+) and r0 cells and both cell lines were resistant to mitochondrial oxidation, loss of mitochondrial membrane potential and cell death in response to the GSH depleting agent DEM. These results show that OPZ is an effective inducer of the phase 2 response in CEM cells and confers protection against electrophile-induced oxidative stress and cell death. Furthermore,the OPZ-mediated phase 2 response and cellular protection was intact in cells lacking mtDNA, suggesting a mitochondria-independent mechanism for the NRF2 activation by OPZ.