Abstract
Carcinogenesis is blocked by an extraordinary variety of agents belonging to many different classes--e.g., phenolic antioxidants, azo dyes, polycyclic aromatics, flavonoids, coumarins, cinnamates, indoles, isothiocyanates, 1,2-dithiol-3-thiones, and thiocarbamates. The only known common property of these anticarcinogens is their ability to elevate in animal cells the activities of enzymes that inactivate the reactive electrophilic forms of carcinogens. Structure-activity studies on the induction of quinone reductase [NAD(P)H:(quinone-acceptor) oxidoreductase, EC 1.6.99.2] and glutathione S-transferases have revealed that many anti-carcinogenic enzyme inducers contain a distinctive and hitherto unrecognized chemical feature (or acquire this feature after metabolism) that regulates the synthesis of these protective enzymes. The inducers are Michael reaction acceptors characterized by olefinic (or acetylenic) bonds that are rendered electrophilic (positively charged) by conjugation with electron-withdrawing substrates. The potency of inducers parallels their efficiency in Michael reactions. Many inducers are also substrates for glutathione S-transferases, which is further evidence for their electrophilicity. These generalizations have not only provided mechanistic insight into the perplexing question of how such seemingly unrelated anticarcinogens induce chemoprotective enzymes, but also have led to the prediction of the structures of inducers with potential chemoprotective activity.
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- Ansher S. S., Dolan P., Bueding E. Biochemical effects of dithiolthiones. Food Chem Toxicol. 1986 May;24(5):405–415. doi: 10.1016/0278-6915(86)90205-x. [DOI] [PubMed] [Google Scholar]
- Benson A. M., Barretto P. B. Effects of disulfiram, diethyldithiocarbamate, bisethylxanthogen, and benzyl isothiocyanate on glutathione transferase activities in mouse organs. Cancer Res. 1985 Sep;45(9):4219–4223. [PubMed] [Google Scholar]
- Benson A. M., Barretto P. B., Stanley J. S. Induction of DT-diaphorase by anticarcinogenic sulfur compounds in mice. J Natl Cancer Inst. 1986 Mar;76(3):467–473. [PubMed] [Google Scholar]
- Boyland E., Chasseaud L. F. Enzyme-catalysed conjugations of glutathione with unsaturated compounds. Biochem J. 1967 Jul;104(1):95–102. doi: 10.1042/bj1040095. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Boyland E., Chasseaud L. F. Enzymes catalysing conjugations of glutathione with alpha-beta-unsaturated carbonyl compounds. Biochem J. 1968 Oct;109(4):651–661. doi: 10.1042/bj1090651. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Brüsewitz G., Cameron B. D., Chasseaud L. F., Görler K., Hawkins D. R., Koch H., Mennicke W. H. The metabolism of benzyl isothiocyanate and its cysteine conjugate. Biochem J. 1977 Jan 15;162(1):99–107. doi: 10.1042/bj1620099. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chasseaud L. F. The role of glutathione and glutathione S-transferases in the metabolism of chemical carcinogens and other electrophilic agents. Adv Cancer Res. 1979;29:175–274. doi: 10.1016/s0065-230x(08)60848-9. [DOI] [PubMed] [Google Scholar]
- De Long M. J., Dolan P., Santamaria A. B., Bueding E. 1,2-Dithiol-3-thione analogs: effects on NAD(P)H:quinone reductase and glutathione levels in murine hepatoma cells. Carcinogenesis. 1986 Jun;7(6):977–980. doi: 10.1093/carcin/7.6.977. [DOI] [PubMed] [Google Scholar]
- De Long M. J., Prochaska H. J., Talalay P. Induction of NAD(P)H:quinone reductase in murine hepatoma cells by phenolic antioxidants, azo dyes, and other chemoprotectors: a model system for the study of anticarcinogens. Proc Natl Acad Sci U S A. 1986 Feb;83(3):787–791. doi: 10.1073/pnas.83.3.787. [DOI] [PMC free article] [PubMed] [Google Scholar]
- De Long M. J., Prochaska H. J., Talalay P. Tissue-specific induction patterns of cancer-protective enzymes in mice by tert-butyl-4-hydroxyanisole and related substituted phenols. Cancer Res. 1985 Feb;45(2):546–551. [PubMed] [Google Scholar]
- Feuer G., Kellen J. A., Kovacs K. Suppression of 7,12-dimethylbenz(alpha) anthracene-induced breast carcinoma by coumarin in the rat. Oncology. 1976;33(1):35–39. doi: 10.1159/000225098. [DOI] [PubMed] [Google Scholar]
- Jakoby W. B. The glutathione S-transferases: a group of multifunctional detoxification proteins. Adv Enzymol Relat Areas Mol Biol. 1978;46:383–414. doi: 10.1002/9780470122914.ch6. [DOI] [PubMed] [Google Scholar]
- Kalantar-Nayestanaki N, Baghaei H, Bertozzi W, Dixit S, Finn JM, Hyde-Wright CE, Kowalski S, Lourie RW, Sargent CP, Ulmer PE. Magnetic structure of 17O at high momentum. Phys Rev Lett. 1988 Apr 25;60(17):1707–1710. doi: 10.1103/PhysRevLett.60.1707. [DOI] [PubMed] [Google Scholar]
- Kensler T. W., Egner P. A., Dolan P. M., Groopman J. D., Roebuck B. D. Mechanism of protection against aflatoxin tumorigenicity in rats fed 5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione (oltipraz) and related 1,2-dithiol-3-thiones and 1,2-dithiol-3-ones. Cancer Res. 1987 Aug 15;47(16):4271–4277. [PubMed] [Google Scholar]
- Kuroda K., Kanisawa M., Akao M. Inhibitory effect of fumaric acid on forestomach and lung carcinogenesis by a 5-nitrofuran naphthyridine derivative in mice. J Natl Cancer Inst. 1982 Dec;69(6):1317–1320. [PubMed] [Google Scholar]
- Kuroda K., Terao K., Akao M. Inhibitory effect of fumaric acid on 3-methyl-4'-(dimethylamino)-azobenzene-induced hepatocarcinogenesis in rats. J Natl Cancer Inst. 1983 Oct;71(4):855–857. [PubMed] [Google Scholar]
- Mennicke W. H., Görler K., Krumbiegel G. Metabolism of some naturally occurring isothiocyanates in the rat. Xenobiotica. 1983 Apr;13(4):203–207. doi: 10.3109/00498258309052256. [DOI] [PubMed] [Google Scholar]
- Prochaska H. J., Bregman H. S., De Long M. J., Talalay P. Specificity of induction of cancer protective enzymes by analogues of tert-butyl-4-hydroxyanisole (BHA). Biochem Pharmacol. 1985 Nov 1;34(21):3909–3914. doi: 10.1016/0006-2952(85)90443-5. [DOI] [PubMed] [Google Scholar]
- Prochaska H. J., De Long M. J., Talalay P. On the mechanisms of induction of cancer-protective enzymes: a unifying proposal. Proc Natl Acad Sci U S A. 1985 Dec;82(23):8232–8236. doi: 10.1073/pnas.82.23.8232. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Prochaska H. J., Santamaria A. B. Direct measurement of NAD(P)H:quinone reductase from cells cultured in microtiter wells: a screening assay for anticarcinogenic enzyme inducers. Anal Biochem. 1988 Mar;169(2):328–336. doi: 10.1016/0003-2697(88)90292-8. [DOI] [PubMed] [Google Scholar]
- Prochaska H. J., Talalay P. Regulatory mechanisms of monofunctional and bifunctional anticarcinogenic enzyme inducers in murine liver. Cancer Res. 1988 Sep 1;48(17):4776–4782. [PubMed] [Google Scholar]
- Sparnins V. L., Barany G., Wattenberg L. W. Effects of organosulfur compounds from garlic and onions on benzo[a]pyrene-induced neoplasia and glutathione S-transferase activity in the mouse. Carcinogenesis. 1988 Jan;9(1):131–134. doi: 10.1093/carcin/9.1.131. [DOI] [PubMed] [Google Scholar]
- Sparnins V. L., Chuan J., Wattenberg L. W. Enhancement of glutathione S-transferase activity of the esophagus by phenols, lactones, and benzyl isothiocyanate. Cancer Res. 1982 Apr;42(4):1205–1207. [PubMed] [Google Scholar]
- Sparnins V. L., Venegas P. L., Wattenberg L. W. Glutathione S-transferase activity: enhancement by compounds inhibiting chemical carcinogenesis and by dietary constituents. J Natl Cancer Inst. 1982 Mar;68(3):493–496. [PubMed] [Google Scholar]
- Sparnins V. L., Wattenberg L. W. Enhancement of glutathione S-transferase activity of the mouse forestomach by inhibitors of Benzo[a]pyrene-induced neoplasia of the forestomach. J Natl Cancer Inst. 1981 Apr;66(4):769–771. [PubMed] [Google Scholar]
- Wattenberg L. W., Bueding E. Inhibitory effects of 5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione (Oltipraz) on carcinogenesis induced by benzo[a]pyrene, diethylnitrosamine and uracil mustard. Carcinogenesis. 1986 Aug;7(8):1379–1381. doi: 10.1093/carcin/7.8.1379. [DOI] [PubMed] [Google Scholar]
- Wattenberg L. W. Chemoprevention of cancer. Cancer Res. 1985 Jan;45(1):1–8. [PubMed] [Google Scholar]
- Wattenberg L. W. Inhibition of carcinogenic effects of polycyclic hydrocarbons by benzyl isothiocyanate and related compounds. J Natl Cancer Inst. 1977 Feb;58(2):395–398. doi: 10.1093/jnci/58.2.395. [DOI] [PubMed] [Google Scholar]
- Wattenberg L. W. Inhibition of neoplasia by minor dietary constituents. Cancer Res. 1983 May;43(5 Suppl):2448s–2453s. [PubMed] [Google Scholar]
- Wattenberg L. W., Lam L. K., Fladmoe A. V. Inhibition of chemical carcinogen-induced neoplasia by coumarins and alpha-angelicalactone. Cancer Res. 1979 May;39(5):1651–1654. [PubMed] [Google Scholar]