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. 1997 Jun;105(Suppl 4):965–970. doi: 10.1289/ehp.97105s4965

Chemoprevention by inducers of carcinogen detoxication enzymes.

T W Kensler 1
PMCID: PMC1470026  PMID: 9255588

Abstract

One of the major mechanisms of chemical protection against carcinogenesis, mutagenesis, and other forms of toxicity mediated by electrophiles is the induction of enzymes involved in their metabolism, particularly phase 2 enzymes such as glutathione S-transferases (GSTs), uridine diphosphate-glucuronosyltransferases, and NAD(P)H:quinone reductase. Furthermore, induction of phase 2 enzymes appears to be a sufficient condition for obtaining chemoprevention and can be achieved in many target tissues by administering any of a diverse array of naturally occurring and synthetic chemical agents. One class of chemopreventive agents, 1,2-dithiole-3-thiones, was developed on the basis of their potent activity in rodent tissues as inducers of GSTs. A substituted dithiolethione, oltipraz [4-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione], is an effective inhibitor of aflatoxin B1-mediated hepatocarcinogenesis in the rat. Oltipraz produces dramatic decreases in the levels of aflatoxin-DNA adducts in the liver as well as in the urinary levels of the depurination product aflatoxin-N7-guanine. Corresponding increases are seen in the biliary elimination of aflatoxin-glutathione conjugates. Administration of oltipraz results in 3- to 4-fold increases in hepatic cytosolic GST activities and mRNA levels for some alpha, mu and pi isoforms. Nuclear run-on assays have indicated that oltipraz treatment elevates rates of transcription of some GST subunits. In the rat, induction of phase 2 enzymes by oltipraz is mediated, at least in part, through the antioxidant response element in the 5' flanking region of these genes. Although oltipraz has a very short plasma half-life, elevations in the levels of some GST isoforms can persist up to 1 week after dosing with oltipraz. Concordantly, intermittent dosing schedules (i.e., once a week) are nearly as effective as daily interventions for inhibition of aflatoxin-mediated hepatic tumorigenesis. The protective efficacy of daily and weekly administration of oltipraz to people in Qidong, People's Republic of China, who are at high risk for aflatoxin exposure and subsequent development of hepetocellular carcinoma, is currently under evaluation.

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Selected References

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  1. Benson A. B., 3rd Oltipraz: a laboratory and clinical review. J Cell Biochem Suppl. 1993;17F:278–291. doi: 10.1002/jcb.240531041. [DOI] [PubMed] [Google Scholar]
  2. Benson A. M., Batzinger R. P., Ou S. Y., Bueding E., Cha Y. N., Talalay P. Elevation of hepatic glutathione S-transferase activities and protection against mutagenic metabolites of benzo(a)pyrene by dietary antioxidants. Cancer Res. 1978 Dec;38(12):4486–4495. [PubMed] [Google Scholar]
  3. Benson A. M., Cha Y. N., Bueding E., Heine H. S., Talalay P. Elevation of extrahepatic glutathione S-transferase and epoxide hydratase activities by 2(3)-tert-butyl-4-hydroxyanisole. Cancer Res. 1979 Aug;39(8):2971–2977. [PubMed] [Google Scholar]
  4. Benson A. M., Hunkeler M. J., Morrow J. F. Kinetics of glutathione transferase, glutathione transferase messenger RNA, and reduced nicotinamide adenine dinucleotide (phosphate):quinone reductase induction by 2(3)-tert-butyl-4-hydroxyanisole in mice. Cancer Res. 1984 Nov;44(11):5256–5261. [PubMed] [Google Scholar]
  5. Bogaards J. J., Verhagen H., Willems M. I., van Poppel G., van Bladeren P. J. Consumption of Brussels sprouts results in elevated alpha-class glutathione S-transferase levels in human blood plasma. Carcinogenesis. 1994 May;15(5):1073–1075. doi: 10.1093/carcin/15.5.1073. [DOI] [PubMed] [Google Scholar]
  6. Bueding E., Dolan P., Leroy J. P. The antischistosomal activity of oltipraz. Res Commun Chem Pathol Pharmacol. 1982 Aug;37(2):293–303. [PubMed] [Google Scholar]
  7. Buetler T. M., Gallagher E. P., Wang C., Stahl D. L., Hayes J. D., Eaton D. L. Induction of phase I and phase II drug-metabolizing enzyme mRNA, protein, and activity by BHA, ethoxyquin, and oltipraz. Toxicol Appl Pharmacol. 1995 Nov;135(1):45–57. doi: 10.1006/taap.1995.1207. [DOI] [PubMed] [Google Scholar]
  8. Cabral J. R., Neal G. E. The inhibitory effects of ethoxyquin on the carcinogenic action of aflatoxin B1 in rats. Cancer Lett. 1983 Jun;19(2):125–132. doi: 10.1016/0304-3835(83)90146-5. [DOI] [PubMed] [Google Scholar]
  9. Conney A. H. Induction of microsomal enzymes by foreign chemicals and carcinogenesis by polycyclic aromatic hydrocarbons: G. H. A. Clowes Memorial Lecture. Cancer Res. 1982 Dec;42(12):4875–4917. [PubMed] [Google Scholar]
  10. Davidson N. E., Egner P. A., Kensler T. W. Transcriptional control of glutathione S-transferase gene expression by the chemoprotective agent 5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione (oltipraz) in rat liver. Cancer Res. 1990 Apr 15;50(8):2251–2255. [PubMed] [Google Scholar]
  11. De Flora S., Ramel C. Mechanisms of inhibitors of mutagenesis and carcinogenesis. Classification and overview. Mutat Res. 1988 Dec;202(2):285–306. doi: 10.1016/0027-5107(88)90193-5. [DOI] [PubMed] [Google Scholar]
  12. Egner P. A., Gange S. J., Dolan P. M., Groopman J. D., Muñoz A., Kensler T. W. Levels of aflatoxin-albumin biomarkers in rat plasma are modulated by both long-term and transient interventions with oltipraz. Carcinogenesis. 1995 Aug;16(8):1769–1773. doi: 10.1093/carcin/16.8.1769. [DOI] [PubMed] [Google Scholar]
  13. Egner P. A., Kensler T. W., Prestera T., Talalay P., Libby A. H., Joyner H. H., Curphey T. J. Regulation of phase 2 enzyme induction by oltipraz and other dithiolethiones. Carcinogenesis. 1994 Feb;15(2):177–181. doi: 10.1093/carcin/15.2.177. [DOI] [PubMed] [Google Scholar]
  14. Fisher J. M., Wu L., Denison M. S., Whitlock J. P., Jr Organization and function of a dioxin-responsive enhancer. J Biol Chem. 1990 Jun 15;265(17):9676–9681. [PubMed] [Google Scholar]
  15. Friling R. S., Bensimon A., Tichauer Y., Daniel V. Xenobiotic-inducible expression of murine glutathione S-transferase Ya subunit gene is controlled by an electrophile-responsive element. Proc Natl Acad Sci U S A. 1990 Aug;87(16):6258–6262. doi: 10.1073/pnas.87.16.6258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gordon G. B., Prochaska H. J., Yang L. Y. Induction of NAD(P)H:quinone reductase in human peripheral blood lymphocytes. Carcinogenesis. 1991 Dec;12(12):2393–2396. doi: 10.1093/carcin/12.12.2393. [DOI] [PubMed] [Google Scholar]
  17. Groopman J. D., Zhu J. Q., Donahue P. R., Pikul A., Zhang L. S., Chen J. S., Wogan G. N. Molecular dosimetry of urinary aflatoxin-DNA adducts in people living in Guangxi Autonomous Region, People's Republic of China. Cancer Res. 1992 Jan 1;52(1):45–52. [PubMed] [Google Scholar]
  18. Gupta E., Olopade O. I., Ratain M. J., Mick R., Baker T. M., Berezin F. K., Benson A. B., 3rd, Dolan M. E. Pharmacokinetics and pharmacodynamics of oltipraz as a chemopreventive agent. Clin Cancer Res. 1995 Oct;1(10):1133–1138. [PubMed] [Google Scholar]
  19. Jacobson L. P., Zhang B. C., Zhu Y. R., Wang J. B., Wu Y., Zhang Q. N., Yu L. Y., Qian G. S., Kuang S. Y., Li Y. F. Oltipraz chemoprevention trial in Qidong, People's Republic of China: study design and clinical outcomes. Cancer Epidemiol Biomarkers Prev. 1997 Apr;6(4):257–265. [PubMed] [Google Scholar]
  20. Jaiswal A. K. Antioxidant response element. Biochem Pharmacol. 1994 Aug 3;48(3):439–444. doi: 10.1016/0006-2952(94)90272-0. [DOI] [PubMed] [Google Scholar]
  21. Kelloff G. J., Crowell J. A., Boone C. W., Steele V. E., Lubet R. A., Greenwald P., Alberts D. S., Covey J. M., Doody L. A., Knapp G. G. Clinical development plan: oltipraz. J Cell Biochem Suppl. 1994;20:205–218. [PubMed] [Google Scholar]
  22. 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]
  23. Kensler T. W., Helzlsouer K. J. Oltipraz: clinical opportunities for cancer chemoprevention. p. J Cell Biochem Suppl. 1995;22:101–107. doi: 10.1002/jcb.240590813. [DOI] [PubMed] [Google Scholar]
  24. Lam L. K., Sparnins V. L., Wattenberg L. W. Isolation and identification of kahweol palmitate and cafestol palmitate as active constituents of green coffee beans that enhance glutathione S-transferase activity in the mouse. Cancer Res. 1982 Apr;42(4):1193–1198. [PubMed] [Google Scholar]
  25. Langouët S., Coles B., Morel F., Becquemont L., Beaune P., Guengerich F. P., Ketterer B., Guillouzo A. Inhibition of CYP1A2 and CYP3A4 by oltipraz results in reduction of aflatoxin B1 metabolism in human hepatocytes in primary culture. Cancer Res. 1995 Dec 1;55(23):5574–5579. [PubMed] [Google Scholar]
  26. Maxuitenko Y. Y., MacMillan D. L., Kensler T. W., Roebuck B. D. Evaluation of the post-initiation effects of oltipraz on aflatoxin B1-induced preneoplastic foci in a rat model of hepatic tumorigenesis. Carcinogenesis. 1993 Nov;14(11):2423–2425. doi: 10.1093/carcin/14.11.2423. [DOI] [PubMed] [Google Scholar]
  27. Miners J. O., Attwood J., Birkett D. J. Determinants of acetaminophen metabolism: effect of inducers and inhibitors of drug metabolism on acetaminophen's metabolic pathways. Clin Pharmacol Ther. 1984 Apr;35(4):480–486. doi: 10.1038/clpt.1984.64. [DOI] [PubMed] [Google Scholar]
  28. Morel F., Fardel O., Meyer D. J., Langouet S., Gilmore K. S., Meunier B., Tu C. P., Kensler T. W., Ketterer B., Guillouzo A. Preferential increase of glutathione S-transferase class alpha transcripts in cultured human hepatocytes by phenobarbital, 3-methylcholanthrene, and dithiolethiones. Cancer Res. 1993 Jan 15;53(2):231–234. [PubMed] [Google Scholar]
  29. Pantuck E. J., Pantuck C. B., Garland W. A., Min B. H., Wattenberg L. W., Anderson K. E., Kappas A., Conney A. H. Stimulatory effect of brussels sprouts and cabbage on human drug metabolism. Clin Pharmacol Ther. 1979 Jan;25(1):88–95. doi: 10.1002/cpt197925188. [DOI] [PubMed] [Google Scholar]
  30. Park B. K., Kitteringham N. R. Assessment of enzyme induction and enzyme inhibition in humans: toxicological implications. Xenobiotica. 1990 Nov;20(11):1171–1185. doi: 10.3109/00498259009046837. [DOI] [PubMed] [Google Scholar]
  31. Pearson W. R., Reinhart J., Sisk S. C., Anderson K. S., Adler P. N. Tissue-specific induction of murine glutathione transferase mRNAs by butylated hydroxyanisole. J Biol Chem. 1988 Sep 15;263(26):13324–13332. [PubMed] [Google Scholar]
  32. Pearson W. R., Windle J. J., Morrow J. F., Benson A. M., Talalay P. Increased synthesis of glutathione S-transferases in response to anticarcinogenic antioxidants. Cloning and measurement of messenger RNA. J Biol Chem. 1983 Feb 10;258(3):2052–2062. [PubMed] [Google Scholar]
  33. Prestera T., Holtzclaw W. D., Zhang Y., Talalay P. Chemical and molecular regulation of enzymes that detoxify carcinogens. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2965–2969. doi: 10.1073/pnas.90.7.2965. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Primiano T., Egner P. A., Sutter T. R., Kelloff G. J., Roebuck B. D., Kensler T. W. Intermittent dosing with oltipraz: relationship between chemoprevention of aflatoxin-induced tumorigenesis and induction of glutathione S-transferases. Cancer Res. 1995 Oct 1;55(19):4319–4324. [PubMed] [Google Scholar]
  35. 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]
  36. 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]
  37. Prochaska H. J., Fernandes C. L. Elevation of serum phase II enzymes by anticarcinogenic enzyme inducers: markers for a chemoprotected state? Carcinogenesis. 1993 Dec;14(12):2441–2445. doi: 10.1093/carcin/14.12.2441. [DOI] [PubMed] [Google Scholar]
  38. 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]
  39. Raney K. D., Meyer D. J., Ketterer B., Harris T. M., Guengerich F. P. Glutathione conjugation of aflatoxin B1 exo- and endo-epoxides by rat and human glutathione S-transferases. Chem Res Toxicol. 1992 Jul-Aug;5(4):470–478. doi: 10.1021/tx00028a004. [DOI] [PubMed] [Google Scholar]
  40. Roebuck B. D., Liu Y. L., Rogers A. E., Groopman J. D., Kensler T. W. Protection against aflatoxin B1-induced hepatocarcinogenesis in F344 rats by 5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione (oltipraz): predictive role for short-term molecular dosimetry. Cancer Res. 1991 Oct 15;51(20):5501–5506. [PubMed] [Google Scholar]
  41. Rushmore T. H., King R. G., Paulson K. E., Pickett C. B. Regulation of glutathione S-transferase Ya subunit gene expression: identification of a unique xenobiotic-responsive element controlling inducible expression by planar aromatic compounds. Proc Natl Acad Sci U S A. 1990 May;87(10):3826–3830. doi: 10.1073/pnas.87.10.3826. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Scholl P., Musser S. M., Kensler T. W., Groopman J. D. Inhibition of aflatoxin Ml excretion in rat urine during dietary intervention with oltipraz. Carcinogenesis. 1996 Jun;17(6):1385–1388. doi: 10.1093/carcin/17.6.1385. [DOI] [PubMed] [Google Scholar]
  43. Sreerama L., Hedge M. W., Sladek N. E. Identification of a class 3 aldehyde dehydrogenase in human saliva and increased levels of this enzyme, glutathione S-transferases, and DT-diaphorase in the saliva of subjects who continually ingest large quantities of coffee or broccoli. Clin Cancer Res. 1995 Oct;1(10):1153–1163. [PubMed] [Google Scholar]
  44. Talalay P., De Long M. J., Prochaska H. J. Identification of a common chemical signal regulating the induction of enzymes that protect against chemical carcinogenesis. Proc Natl Acad Sci U S A. 1988 Nov;85(21):8261–8265. doi: 10.1073/pnas.85.21.8261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Wang J. S., Qian G. S., Zarba A., He X., Zhu Y. R., Zhang B. C., Jacobson L., Gange S. J., Muñoz A., Kensler T. W. Temporal patterns of aflatoxin-albumin adducts in hepatitis B surface antigen-positive and antigen-negative residents of Daxin, Qidong County, People's Republic of China. Cancer Epidemiol Biomarkers Prev. 1996 Apr;5(4):253–261. [PubMed] [Google Scholar]
  46. Wattenberg L. W. Chemoprevention of cancer. Cancer Res. 1985 Jan;45(1):1–8. [PubMed] [Google Scholar]
  47. Williams G. M., Tanaka T., Maeura Y. Dose-related inhibition of aflatoxin B1 induced hepatocarcinogenesis by the phenolic antioxidants, butylated hydroxyanisole and butylated hydroxytoluene. Carcinogenesis. 1986 Jul;7(7):1043–1050. doi: 10.1093/carcin/7.7.1043. [DOI] [PubMed] [Google Scholar]
  48. Zhang Y., Kensler T. W., Cho C. G., Posner G. H., Talalay P. Anticarcinogenic activities of sulforaphane and structurally related synthetic norbornyl isothiocyanates. Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3147–3150. doi: 10.1073/pnas.91.8.3147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Zhang Y., Talalay P., Cho C. G., Posner G. H. A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure. Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2399–2403. doi: 10.1073/pnas.89.6.2399. [DOI] [PMC free article] [PubMed] [Google Scholar]

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