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Mechanisms of induction of cancer-protective enzymes: a unifying proposal

Journal Article · · Proc. Natl. Acad. Sci. U.S.A.; (United States)
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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 can protect against the toxicities of quinones and is a useful marker for protective enzyme induction. Quinone reductase can be induced in murine Hepa 1c1c7 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) induced quinone reductase in these systems, but resorcinol (1,3-diphenol) and its substituted analogues are inactive. Furthermore, 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 liability. The observations that some chemoprotective compounds (e.g., azo dyes, ..beta..-naphthoflavone) induced both cytochromes P-450 and quinone reductase, whereas others (e.g., tert-butylhyrodquinone) 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.

Research Organization:
Johns Hopkins Univ. School of Medicine, Baltimore, MD
OSTI ID:
6135233
Journal Information:
Proc. Natl. Acad. Sci. U.S.A.; (United States), Journal Name: Proc. Natl. Acad. Sci. U.S.A.; (United States) Vol. 82:23; ISSN PNASA
Country of Publication:
United States
Language:
English

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Related Subjects

560301* -- Chemicals Metabolism & Toxicology-- Cells-- (-1987)
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
AMINES
ANIMAL CELLS
ANIMALS
ANTIOXIDANTS
AROMATICS
AZO COMPOUNDS
AZO DYES
CARCINOGENS
CHEMICAL REACTIONS
COENZYMES
CONNECTIVE TISSUE CELLS
DYES
ENZYME ACTIVITY
ENZYMES
FIBROBLASTS
HYDROXY COMPOUNDS
MAMMALS
MICE
MUTAGENS
NADP
NUCLEOTIDES
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
OXIDOREDUCTASES
PHENOLS
QUINONES
REDOX REACTIONS
RODENTS
SOMATIC CELLS
TOXICITY
TUMOR CELLS
VERTEBRATES