Oltipraz is a bifunctional inducer activating both phase I and phase II drug-metabolizing enzymes via the xenobiotic responsive element.

摘要: Oltipraz, a promising cancer chemopreventive agent, has been recognized as monofunctional inducer selectively activating phase II carcinogen-detoxifying enzymes via the antioxidant responsive element (ARE). However, we report here that oltipraz also induces rat glutathione S-transferase A5 (GSTA5), potent detoxifying enzyme, by means of xenobiotic (XRE). Although an ARE sequence exists in 5' upstream rGSTA5 gene, this cis-acting regulatory loses its responsiveness to treatment because extensive mutations distal-half site. Our data indicate XRE sequence, located downstream transcription initiation site is another oltipraz-responsive element. Electrophoretic mobility shift assay showed steadily XRE-aryl hydrocarbon receptor (AhR) binding, which can be blocked specifically excess oligonucleotides or AhR antibody. By cloning different XREs into pGL3-promoter vector, found activate enhancers from several drug metabolism enzymes, including rGSTA5, rGSTA2, NAD(P)H:quinone reductase, and it activates I enzyme CYP1A1. Oltipraz's effect on AhR-dependent independent presence active Reverse transcriptase-polymerase chain reaction experiments revealed gene expression both drug-metabolizing hepatoma cells. Thus, conclude that, like ARE, pathway constitutes important part molecular mechanism contributing oltipraz-induced enzymes. Oltipraz bifunctional inducer, modulating enhance carcinogen detoxification.