| Abstract: |
The induction of electrophile-processing (Phase II) enzymes is a major mechanism whereby a surprisingly wide variety of compounds can inhibit the development of carcinogen-induced neoplasms. By using the induction of NAD(P)H:quinone reductase (EC 1.6.99.2; QR) in Hepa 1c1c7 murine hepatoma cells as an indicator of Phase II enzyme regulation, we tested a series of analogues of BHA [2(3)-tert-butyl-4-hydroxyanisole] as inducers. Whereas all 1,2-and 1,4-diphenols examined were inducers, 1,3-diphenols were completely inactive. Since 1,2-and 1,4-diphenols are chemically related in that they can undergo facile oxidations to quinones, whereas 1,3-diphenols cannot, we concluded that the signal for induction is chemically mediated. Extension of these structure-activity studies to other chemical classes of anticarcinogenic inducers showed that the presence or acquisition of a Michael acceptor function or equivalent electrophilic center is responsible for the inductive signal. This insight has permitted the prediction of structures of compounds with inductive activity. These generalizations hold promise for the design of more potent and less toxic anticarcinogenic enzyme inducers. |
