REGULATION OF PHASE 2 ENZYME-INDUCTION BY OLTIPRAZ AND OTHER DITHIOLETHIONES

4-Methyl-5-pyrazinyl-3H-1,2-dithiole-3-thione (oltipraz) and several o ther dithiolethiones protect against the acute toxicities of many xeno biotics and are effective inhibitors of experimental carcinogenesis. T hese protective effects are mediated, in part, through elevation of gl utathione S-transferase, NAD(P)H: quinone reductase and UDP-glucuronos yltransferase activities in the liver and other target tissues. The in duction of these phase 2 enzymes by oltipraz results from enhanced tra nscription. In the present study, the molecular mechanisms of these in ductions were analyzed utilizing a construct containing a 41 bp enhanc er element derived from the 5'-upstream region of the mouse liver glut athione S-transferase Ya subunit gene ligated to the 5' end of the iso lated promoter region of this gene, and inserted into a plasmid contai ning a human growth hormone reporter gene. When this construct was tra nsfected into murine Hepa 1c1c7 hepatoma cells, the concentrations of 25 dithiolethiones and related analogs required to double growth hormo ne production were determined and spanned a range nearly three orders of magnitude. Concentrations of dithiolethiones required to double the specific activity of NAD(P)H:quinone reductase were also determined i n Hepa 1c1c7 cells. There was a positive correlation (r = 0.78) betwee n the potencies of the 21 active compounds as inducers of both NAD(P)H :quinone reductase activity and growth hormone production. Moreover, n o dithiolethiones were inactive in only one system. It is probable, th erefore, that the induction of NAD(P)H:quinone reductase and other pha se 2 enzymes by oltipraz and other dithiolethiones is mediated entirel y through the 41 bp enhancer element.