Chemoprotection against cancer by induction of phase 2 enzymes.
Induction of Phase 2 enzymes is an effective and sufficient strategy for achieving protection against the toxic and neoplastic effects of many carcinogens. It is proposed that the concept of Phase 2 enzymes as being responsible only for the conjugation of functionalized xenobiotics with endogenous cellular ligands such as glutathione (glutathione S-transferases) and glucuronic acid (UDP-glucuronosyltransferases) be expanded to include proteins with the following common characteristics: (a) coordinate induction by a broad range of chemical agents that all have the capacity to react with sulfhydryl groups; (b) possible regulation by common promoter elements; and (c) catalysis of reactions that lead to comprehensive protection against electrophile and reactive oxygen toxicities, by a wide variety of mechanisms. These mechanisms include: conjugation with endogenous ligands, chemical modification of reactive features of molecules that can damage DNA and other macromolecules, and generation or augementation of cellular antioxidants. In addition to the above conjugating enzymes, a provisional and partial list of Phase 2 proteins might include: NAD(P)H:quinone reductase, epoxide hydrolase, dihydrodiol dehydrogenase, gamma-glutamylcysteine synthetase, heme oxygenase-1, leukotriene B4 dehydrogenase, aflatoxin B1 dehydrogenase, and ferritin.
Talalay
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Department of Pharmacology and Molecular Sciences, The Johns Hopkins Universit, School of Medicine, Baltimore, MD 21205, USA. ptalalay@jhmi.edu
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004790:Enzyme Induction / Q000187:drug effects*; D014453:Glucuronosyltransferase / Q000378:metabolism; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006801:Humans; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D009369:Neoplasms / Q000517:prevention & control*; D051381:Rats
D016588:Anticarcinogenic Agents; D006419:Heme Oxygenase (Decyclizing); D016660:NAD(P)H Dehydrogenase (Quinone); D014453:Glucuronosyltransferase; D005982:Glutathione Transferase; D005721:Glutamate-Cysteine Ligase