On the mechanisms of induction of cancer-protective enzymes: a unifying proposal.

Abstract

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...

Anticarcinogenic Factors in Plant Foods: A New Class of Nutrients?

“…QR is often considered as a phase I1 enzyme, and a unifying theory for induction of phase I and phase I1 enzymes has been presented (Prochaska et al 1985), postulating that inducers fall into two classes -bifunctional (induce phase I and I1 enzymes) and monofunctional (induce phase I1 only). The former include compounds such as benzo(a)pyrene and aflatoxin (Talalay & Prochaska, 1987).…”

“…A rapid and convenient assay for QR has been developed (Prochaska et al 1985;Prochaska & Santamaria, 1988) and a range of inducers has been identified. These include quercetin, coumarin, a-angelicalactone (De Long et al 1986), benzyl isothiocyanate (Talalay & Prochaska, 1987) and sulphoraphane (Zhang et al 1992).…”

“…This figure will form the basis for much of the subsequent discussion. For convenience the metabolic pathway is usually divided into Phase I (which often involves carcinogen activation), Phase I1 (conjugation) and Phase I11 (transport out of the cell: Prochaska et al 1985;Ishikawa, 1992). Paradoxically, the metabolic pathways involved in detoxification may also serve to generate potentially damaging chemical species.…”

Activation of Mitogen-activated Protein Kinase Pathways Induces Antioxidant Response Element-mediated Gene Expression via a Nrf2-dependent Mechanism

“…Such a chemopreventive property of these compounds has been presumably ascribed to the ability of the compounds to induce several detoxifying enzymes, such as glutathione S-transferase (GST) and quinone reductase (14). Subsequent studies revealed that the induction of detoxifying enzyme activity occurs at the transcriptional level and is regulated by a cis-acting element that is present in the promoters of detoxifying enzyme genes defined as an antioxidant response element (ARE) (15) or electrophil response element (16).…”

Structures of recombinant human and mouse NAD(P)H:quinone oxidoreductases: Species comparison and structural changes with substrate binding and release

“…This reaction prevents the one-electron reduction of quinones by cytochrome P450 reductase and other flavoproteins, resulting in oxidative cycling of deleterious radical species. The enzyme is inducible by a wide variety of Michael reaction acceptors and other electrophiles (4,5). In addition to its possible role in the detoxification of dietary quinones, the enzyme has been shown to catalyze the reductive activation of quinolic chemotherapeutic compounds such as mitomycins (6), anthracyclines, and aziridinyl-benzoquinones.…”