Induction of detoxification enzymes is a major mechanism whereby a wide variety of chemical agents protect rodents against neoplastic, mutagenic, and other toxicities of carcinogens. The enzyme NAD(P)H:(quinone acceptor) oxidoreductase (EC 1.6.99.2) can protect against the toxicities of quinones and is a useful marker for protective enzyme induction. Quinone reductase can be induced in murine Hepa lclc7 hepatoma cells and 3T3 embryo fibroblasts by compounds that are chemoprotectors in vivo, including some phenolic antioxidants, azo dyes, aromatic diamines, and aminophenols. Structurally dissimilar catechols (1,2-diphenols) and hydroquinones (1,4-diphenols) induce quinone reductase in these systems, but resorcinol (1,3-diphenol) and its substituted analogues are inactive. Futhermore, only aromatic 1,2-and 1,4-diamines and aminophenols are inducers, whereas the 1,3-diamines are completely inactive. These findings suggest that the functional capacity to form quinones or quinonediimines, rather than the precise structure, is essential for inductive activity and that the generation of the signal for enzyme induction depends upon oxidation-reduction lability.The observations that some chemoprotective compounds (e.g., azo dyes, fi-naphthoflavone) induce both cytochromes P-450 and quinone reductase, whereas others (e.g., tert-butylhydroquinone) induce only quinone reductase, can be reconciled by the fact that inducers of the first type are metabolized by P-450 enzymes to form products that are functionally similar to compounds of the second type.A surprising variety of chemicals protect rodents against neoplastic, mutagenic, and other toxic effects of many types of carcinogens (1, 2). A striking feature of the chemoprotectors is that they belong to totally unrelated chemical classes such as substituted phenols, azo dyes, coumarins, sulfur compounds (disulfiram, isothiocyanates, carbon disulfide), flavones, indoles, retinoids, tocopherols, and selenium compounds (3). Some of these protective substances alter the metabolic fate of carcinogens (4-6) by modulating the activities of either or both phase I and phase II drug-metabolizing enzymest (7)(8)(9)(10)(11)(12)(13)(14)(15). Induction of enzymes that detoxify electrophilic metabolites of carcinogens may interrupt the neoplastic process. Thus, BHA [3(2)-tert-butyl-4-hydroxyanisole], a phenolic antioxidant, which is a widely used food additive and protects against many carcinogens, enhances the hepatic and peripheral activities of several detoxification enzymes, including glutathione S-transferase, NAD(P)H:quinone reductase, epoxide hydrolase, and glucuronide-conjugating systems, and raises the levels of glutathione and enzymes concerned with its reduction (2, 7-10, 14-16).How do so many structurally unrelated compounds induce similar chemoprotective enzymes? We approached this question by examining the relation between structure and inductive activity among three classes of enzyme inducers and chemoprotectors: phenolic antioxidants, aromatic diamines, and azo dyes...