Inducers of Enzymes That Protect Against Carcinogens and Oxidants

Drug- and Food-Based Approaches with Dithiolethiones and Sulforaphane
  • Thomas W. Kensler
  • Paul Talalay
Part of the Cancer Drug Discovery and Development book series (CDD&D)


The multiple stages of carcinogenesis offer many potential strategies for protection. However, in the majority of tests conducted in animal models, protection has been achieved by administering the chemopreventive agent prior to and/or concurrently with the exposure to the carcinogen. Considering this temporal relationship between the administration of anticarcinogen and carcinogen, it seems likely that these agents act at least in part to alter the metabolism and disposition of carcinogens, thereby altering events that are critical to the initial interactions of chemical carcinogens with biomolecules.


Enzyme Inducer Chemopreventive Agent Aberrant Crypt Focus Cruciferous Vegetable Antioxidant Response Element 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Wattenberg LW. Inhibition of carcinogenic and toxic effects of polycyclic hydrocarbons by phenolic antioxidants and ethoxyquin. J Natl Cancer Inst 1972;48:1425–1430.PubMedGoogle Scholar
  2. 2.
    Benson AM, Batzinger RP, Ou S-Y L, et al. Elevation of hepatic GST activities and protection against mutagenic metabolites of B [a]P by dietary antioxidants. Cancer Res 1978;38:4486–4495.PubMedGoogle Scholar
  3. 3.
    Kensler TW. Chemoprevention by inducers of carcinogen detoxication enzymes. Environ Health Perspect 1997;10564:965–970.Google Scholar
  4. 4.
    Fahey JW, Talalay P. Antioxidant functions of sulforaphane: a potent inducer of phase II detoxication enzymes. Food Chem Toxicol 1999;37:973–979.PubMedGoogle Scholar
  5. 5.
    Hayes JD, McLellan LI. Glutathione and glutathionedependent enzymes represent a coordinately regulated defense against oxidative stress. Free Radic Res 1999;31:273–300.PubMedGoogle Scholar
  6. 6.
    Rushmore TH, King RG, Paulson KE, Pickett CB. 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 USA 1990;87:3826–3830.PubMedGoogle Scholar
  7. 7.
    Pearson WB, Windle JJ, Morrow JF, et al. Increased synthesis of glutathione S-transferase in response to anticarcinogenic antioxidants. Cloning and measurement of messenger RNA. J Biol Chem 1983;258:2052–2062.PubMedGoogle Scholar
  8. 8.
    Prochaska HJ, Talalay P. Regulatory mechanisms of monofunctional and bifunctional anticarcinogenic enzyme inducers in murine liver. Cancer Res 1988;48:4776–4782.PubMedGoogle Scholar
  9. 9.
    Fisher JM, Wu L, Denison MS, Whitlock JP, Jr. Organization and function of a dioxin-responsive enhancer. J Biol Chem 1990;265:9676–9681.PubMedGoogle Scholar
  10. 10.
    Langouët S, Coles B, Morel F, et al. Inhibition of CYP 1 A2 and CYP3A4 by oltipraz results in reduction of aflatoxin B 1 metabolism in human hepatocytes in primary culture. Cancer Res 1995;55:5574–5579.PubMedGoogle Scholar
  11. 11.
    Talalay P, DeLong MJ, Prochaska HJ. Identification of a common chemical signal regulating the induction of enzymes that protect against chemical carcinogenesis. Proc Natl Acad Sci USA 1988;85:8261–8265.PubMedGoogle Scholar
  12. 12.
    Prestera T, Holtzclaw WD, Zhang Y, Talalay P. Chemical and molecular regulation of enzymes that detoxify carcinogens. Proc Natl Acad Sci USA 1993;90:2965–2969.PubMedGoogle Scholar
  13. 13.
    Friling RS, Bensimon A, Tichauer Y, Daniel V. Xenobioticinducible expression of murine glutathione S-transferase Ya subunit gene is controlled by an electrophile-responsive element. Proc Natl Acad Sci USA 1990;87:6258–6262.PubMedGoogle Scholar
  14. 14.
    Jaiswal AK. Antioxidant response element. Biochem Pharmacol 1994;48:439–444.PubMedGoogle Scholar
  15. 15.
    Wasserman WW, Fahl WE. Functional antioxidant responsive elements. Proc Natl Acad Sci USA 1997;94:5361–5366.PubMedGoogle Scholar
  16. 16.
    Egner PA, Kensler TW, Prestera T et al. Regulation of phase 2 enzyme induction by oltipraz and other dithiolethiones. Carcinogenesis 1994;15:177–181.PubMedGoogle Scholar
  17. 17.
    Chan JY, Han X, Kan YW. Cloning of Nrf 1, an NF-E2-related transcription factor, by genetic selection in yeast. Proc Natl Acad Sci USA 1993;90:11,366–11,370.Google Scholar
  18. 18.
    Moi P, Chan K, Asunis I, et al. Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the β-globin locus control region. Proc Natl Acad Sci USA 1993;91:9926–9930.Google Scholar
  19. 19.
    Venugopal R, Jaiswal AK. Nrfl and Nrf2 positively and c-Fos and Fra 1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H:quinone oxidoreductase gene. Proc Natl Acad Sci USA 1996;93:14,960–14,965.Google Scholar
  20. 20.
    Itoh K, Chiba T, Takahashi S, et al. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Comm 1997;236:313–322.PubMedGoogle Scholar
  21. 21.
    Kwak M-K, Itoh K, Yamamoto M, et al. Role of transcription factor Nrf2 in the induction of hepatic phase 2 and antioxidative enzymes in vivo by the chemoprotective agent 3H-1,2-dithiole-3-thione. Mol Med 2001;7:135–145.PubMedGoogle Scholar
  22. 22.
    McMahon M, Itoh K, Yamamoto M, et al. The Cap’ n’ Collar basic leucine zipper transcription factor Nrf2 (NF-E2 p45-related factor 2) controls both constitutive and inducible expression of intestinal detoxification and glutathione biosynthetic enzymes. Cancer Res 2001;61:3299–3307.PubMedGoogle Scholar
  23. 23.
    Itoh K, Wakabayashi N, Katoh Y, et al. Keap 1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev 1999;13:76–86.PubMedGoogle Scholar
  24. 24.
    Dinkova-Kostova AT, Holtzclaw WD, Cole RN, et al. Direct evidence that sulfhydryl groups of Keap 1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc Natl Acad Sci USA 2002;99:11,908–11,913.Google Scholar
  25. 25.
    Enomoto A, Itoh K, Nagayoshi E, et al. High sensitivity of Nrf2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes. Toxicol Sci 2001;59:169–177.PubMedGoogle Scholar
  26. 26.
    Chan K, Kan YW. Nrf2 is essential for protection against acute pulmonary injury in mice. Proc Natl Acad Sci USA 1999;96:12,731–12,736.Google Scholar
  27. 27.
    Cho HY, Jedlicka AE, Reddy SPM, et al. Role of nrf2 in protection against hyperoxic lung injury in mice. Am J Respir Cell Mol Biol 2002;26:175–182.PubMedGoogle Scholar
  28. 28.
    Ramos-Gomez M, Kwak MK, Dolan PM, et al. Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor deficient mice. Proc Nall Acad Sci USA 2001;98:3410–3415.Google Scholar
  29. 29.
    Fahey JW, Haristoy X, Dolan PM, et al. Sulforaphane inhibits extracellular, intracellular and antibiotic-resistant strains of Helicobacter pylori and prevents benz[a]pyrene-induced stomach cancers. Proc Natl Acad Sci USA 2002;99:7610–7615.PubMedGoogle Scholar
  30. 30.
    Primiano T, Gastel JA, Kensler TW, Sutter TR. Isolation of cDNAs representing dithiolethione-responsive genes. Carcinogenesis 1996;17:2297–2303.PubMedGoogle Scholar
  31. 31.
    Li J, Lee JM, Johnson JA. Microarray analysis reveals an antioxidant responsive element-driven gene set involved in conferring protection from an oxidative stress-induced apoptosis in IMR-32 cells. J Biol Chem 2002;277:388–394.PubMedGoogle Scholar
  32. 32.
    Thimmulappa RK, Mai KH, Srisuma S, et al. Identification of Nrf2 regulated genes by oligonucleotide microarray: potential role in cancer chemoprevention. Cancer Res 2002;62:5196–5203.PubMedGoogle Scholar
  33. 33.
    Williams RT. Comparative patterns of drug metabolism. Fed Proc 1967;26:1029–1039.PubMedGoogle Scholar
  34. 34.
    Primiano T, Sutter TR, Kensler TW. Redox regulation of genes that protect against carcinogens. Comp Biochem Physiol 1997;118B:487–497.Google Scholar
  35. 35.
    Fahey JW, Talalay PT. Antioxidant functions of sulforaphane: a potent inducer of phase 2 detoxication enzymes. Food Chem Toxicol 1999;37:973–979.PubMedGoogle Scholar
  36. 36.
    Hayes JD, McLellan LI. Glutathione and glutathionedependent enzymes represent a coordinately regulated defense against oxidative stress. Free Radic Res 1999;31:273–300.PubMedGoogle Scholar
  37. 37.
    Guyton KZ, Kensler TW. Oxidative mechanisms in carcinogenesis. Br Med Bull 1993;49:523–544.PubMedGoogle Scholar
  38. 38.
    Gao X, Dinkova-Kostova AT, Talalay P. Powerful and prolonged protection of human retinal pigment epithelial cells, keratinocytes, and mouse leukemia cells against oxidative damage: the indirect antioxidant effects of sulforaphane. Proc Natl Acad Sci USA 2001;98:15,221–15,226.Google Scholar
  39. 39.
    Primiano T, Egner PA, Suter TR, et al. Intermittent dosing with oltipraz: relationship between chemoprevention of aflatoxin-induced tumorigenesis and induction of glutathione S-transferases. Cancer Res 1995;55:4319–4324.PubMedGoogle Scholar
  40. 40.
    Bueding E, Dolan P, Leroy JP. The antischistosomal activity of oltipraz. Res Commun Chem Pathol Pharmacol 1982;37:293–303.PubMedGoogle Scholar
  41. 41.
    Moreau N, Martens T, Fleury MB, Leroy JP. Metabolism of oltipraz and glutathione reductase inhibition. Biochem Pharmacol 1990;40:1299–1305.PubMedGoogle Scholar
  42. 42.
    Mkoji GM, Smith JM, Pritchard RK. Effect of oltipraz on the susceptibility of adult Schistosoma mansoni to killing by mouse peritoneal exudates cells. Parisitol Res 1990;76:435–439.Google Scholar
  43. 43.
    Ansher SS, Dolan P, Bueding E. Biochemical effects of dithiolthiones. Food Chem Toxicol 1986;24:405–415.PubMedGoogle Scholar
  44. 44.
    Ansher SS, Dolan P, Bueding E. Chemoprotective effects of two dithiolethiones and of butylhydroxyanisole against carbon tetrachloride and acetaminophen toxicity. Hepatology 1983;3:932–935.PubMedGoogle Scholar
  45. 45.
    Davies MH, Schamber GJ, Schnell RC. Oltipraz-induced amelioration of acetaminophen hepatotoxicity in hamsters. Toxicol Appl Pharmacol 1991;109:17–28.PubMedGoogle Scholar
  46. 46.
    Liu LY, Roebuck BD, Yager JD, et al. Protection by 5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione (oltipraz) against the hepatotoxicity of aflatoxin B1 in the rat. Toxicol Appl Pharmacol 1988;93:442–451.PubMedGoogle Scholar
  47. 47.
    Bolton MG, Muñoz A, Jacobson LP, et al. Transient intervention with oltipraz protects against aflatoxin-induced hepatic tumorigenesis. Cancer Res 1993;53:3499–3504.PubMedGoogle Scholar
  48. 48.
    Kang KW, Choi SH, Ha JR, et al. Inhibition of dimethylnitrosamine-induced liver fibrosis by [5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione] (oltipraz) in rats: suppression of transforming growth factor-β 1 and tumor necrosis factorα expression. Chem Biol Interactions 2002;139:61–77.Google Scholar
  49. 49.
    Kang KW, Kim YG, Cho MK, et al. Oltipraz regenerates cirrhotic liver through CCAAT/enhancer binding proteinmediated stellate cell inactivation. FASEB J 2002;16:1988–1990.PubMedGoogle Scholar
  50. 50.
    Newberne PM, Harrington DH, Wogan GN. Effects of cirrhosis and other liver insults on induction of liver tumors by aflatoxin in rats. Lab Investig 1966;15:962–969.PubMedGoogle Scholar
  51. 51.
    Wattenberg LW, Bueding E. Inhibitory effects of 5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione (oltipraz) on carcinogenesis induced by B[a]P, diethylnitrosamine and uracil mustard. Carcinogenesis 1986;7:1379–1381.PubMedGoogle Scholar
  52. 52.
    Rao CV, Tokomo K, Kelloff G, Reddy BS. Inhibition by dietary oltipraz of experimental intestinal carcinogenesis induced by azoxymethane in male F344 rats. Carcinogenesis 1991;12:1051–1055.PubMedGoogle Scholar
  53. 53.
    Rao CV, Rivenson A, Katiwalla M, et al. Chemopreventive effect of oltipraz during different stages of experimental colon carcinogenesis induced by azoxymethane in male F344 rats. Cancer Res 1993;53:2505–2506.Google Scholar
  54. 54.
    Clapper ML, Wood M, Leahy K, et al. Chemopreventive activity of oltipraz against N-nitrosobis(2-oxopropyl)amine (BOP)-induced ductal pancreatic carcinoma development and effects on survival of Syrian golden hamsters. Carcinogenesis 1995;16:2159–2165.PubMedGoogle Scholar
  55. 55.
    Moon RC, Kelloff GJ, Detrisac CJ, et al. Chemoprevention of OH-BBN induced bladder cancer in mice by oltipraz, alone or in combination with 4-HPR and DFMO. Anticancer Res 1994;14:5–11.PubMedGoogle Scholar
  56. 56.
    Rao CV, Rivenson A, Zang E, et al. Inhibition of 2-amino1-methyl-6-phenylimidazo[4,5]pyridine-induced lymphoma formation by oltipraz. Cancer Res 1996;56:3395–3398.PubMedGoogle Scholar
  57. 57.
    Moon RC, Rao KVN, Detrisac CJ, et al. Chemoprevention of respiratory tract neoplasia in the hamster by oltipraz, alone and in combination. Int J Oncol 1994;4:661–667.PubMedGoogle Scholar
  58. 58.
    Roebuck BD, Liu YL, Rogers AR, et al. 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;51:5501–5506.PubMedGoogle Scholar
  59. 59.
    Moon RC. Evaluation of chemopreventive agents by in vivo screening assays. Prepared for National Cancer Institute by IIT Research Institute under Contract No. N01-CN-55448–04. Final Report, 1988.Google Scholar
  60. 60.
    Helmes CT, Becker RA, Seidenberg JM, et al. Chemoprevention of mouse skin tumorigenesis by dietary oltipraz. Proc Am Assoc Cancer Res 1989;30:177.Google Scholar
  61. 61.
    Heusse D, Marland M, Bredenbac J, et al. Disposition of 14C-oltipraz in animals. Pharmacokinetics in mice, rats and monkeys. Comparison of the biotransformation in the infected mouse and in schistosomes. Arzneimittelforschung 1985;35:1431–1436.PubMedGoogle Scholar
  62. 62.
    Maxuitenko YY, MacMillan DL, Kensler TW, Roebuck BD. Evaluation of the post-initiation effects of oltipraz on aflatoxin B 1-induced preneoplastic foci in a rat model of hepatic tumorigenesis. Carcinogenesis 1993;14:2423–2425.PubMedGoogle Scholar
  63. 63.
    Kensler TW, Primiano T, Sutter TR, et al. Mechanisms of chemoprotection by 1,2-dithiole-3-thiones8. In Proceedings of the International Symposium on Natural Antioxidants: Molecular Mechanisms and Health Effects. Packer L, Traber MG, Xin W, eds. AOCS Press Champaign IL, 1996:243–250.Google Scholar
  64. 64.
    Reddy BS, Rao CV, Rivenson A,Kelloff GJ. Chemoprevention of colon carcinogenesis by organosulfur compounds. Cancer Res 1993;53:3493–3498.PubMedGoogle Scholar
  65. 65.
    Lubet RA, Steele VC, Eto I, et al. Chemopreventive efficacy of anethole trithione, N-acetyl-L-cysteine, miconazole and phenethylisothiocyanate in the DMBA-induced rat mammary cancer model. Int J Cancer 1997;72:95–101.PubMedGoogle Scholar
  66. 66.
    Archer S. The chemotherapy of schistosomiasis. Annu Rev Pharmacol 1985;25:485–508.Google Scholar
  67. 67.
    Oltipraz-Investigational Drug Brochure, Chemoprevention Branch, National Cancer Institute, 1994.Google Scholar
  68. 68.
    Benson AB III. Oltipraz: a laboratory and clinical review. J Cell Biochem 1993;17F Suppl:278–291.Google Scholar
  69. 69.
    Dimitrov NV, Bennett JL, McMillan J, et al. Clinical pharmacology studies of oltipraz — a potential chemopreventive agent. Invest New Drugs 1992;10: 89–298.Google Scholar
  70. 70.
    O’Dwyer PJ, Szarka C, Brennan JM, et al. Pharmacokinetics of the chemopreventive agent oltipraz and of its metabolite M3 in human subjects after a single oral dose. Clin Cancer Res 2000;6:4692–4696.PubMedGoogle Scholar
  71. 71.
    Pendyala L, Schwartz G, Bolanowska-Higdon W, et al. Phase I/pharmacodynamic study of N-acetylcysteine/ oltipraz in smokers: early termination due to excessive toxicity. Cancer Epidemiol Biomarkers Prey 2001;10:269–272.Google Scholar
  72. 72.
    Jacobson LP, Zhang BC, Zhu YR, et al. Oltipraz Chemoprevention Trial in Qidong, People’s Republic of China: Study Design and Clinical Outcomes. Cancer Epidemiol Biomarkers Prey 1997;6,257–265.Google Scholar
  73. 73.
    Langouët S, Furge LL, Kerriguy N, et al. Inhibition of human cytochrome P450 enzymes by 1,2-dithiole-3-thione, oltipraz, and its derivatives, and sulforaphane. Chem Res Toxicol 2000;13:245–251.PubMedGoogle Scholar
  74. 74.
    Sofowora GG, Choo EF, Mayo YS, Wilkinson GR. In vivo inhibition of human CYP1A2 activity by oltipraz. Cancer Chemother Pharmacol 2001;47:505–510.PubMedGoogle Scholar
  75. 75.
    Morel F, Fardel O, Meyer DJ, et al. Preferential increase of glutathione S-transferase class alpha transcripts in cultured human hepatocytes by phenobarbital, 3-methylcholanthrene and dithiolethiones. Cancer Res 1993;53:231–234.PubMedGoogle Scholar
  76. 76.
    Gupta E, Olopade OI, Ratain MJ, et al. Pharmacokinetics and pharmacodynamics of oltipraz as a chemopreventive agent. Clin Cancer Res 1995;1:1133–1138.PubMedGoogle Scholar
  77. 77.
    O’Dwyer PJ, Szarka CE, Yao KS, et al. Modulation of gene expression in subjects at risk for colorectal cancer by the chemopreventive dithiolethione oltipraz. J Clin Investig 1996;98:1210–1217.PubMedGoogle Scholar
  78. 78.
    Benson AB III, Olopade OI, Ratain MJ, et al. Chronic low dose of 4-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione (oltipraz) in patients with previously resected colon polyps and first-degree relatives of breast cancer patients. Clin Cancer Res 2000;6:3870–3877.PubMedGoogle Scholar
  79. 79.
    Kensler TW, He X, Otieno M, et al. Oltipraz chemoprevention trial in Qidong, People’s Republic of China: modulation of serum aflatoxin albumin adduct biomarkers. Cancer Epidemiol Biomarkers Prey 1998;7:127–134.Google Scholar
  80. 80.
    Wang JS, Shen X, He X, Zhu YR, et al. Protective alterations in phase 1 and 2 metabolism of aflatoxin B by oltipraz in residents of Qidong, People’s Republic of China. J Natl Cancer Inst 1998;91:347–354.Google Scholar
  81. 81.
    Langouët S, Coles B, Morel F, et al. Inhibition of CYP1A2 and CYP3A4 by oltipraz results in reduction of aflatoxin B 1 metabolism in human hepatocytes in primary culture. Cancer Res 1995;55:5574–5579.PubMedGoogle Scholar
  82. 82.
    Kensler TW, Groopman JD, Sutter TR, et al. Development of cancer chemopreventive agents: oltipraz as a paradigm. Chem Res Toxicol 1999;12:113–126.PubMedGoogle Scholar
  83. 83.
    Lam S, MacAulay C, le Riche JC, et al. A randomized phase IIb trial of anethole dithiolethione in smokers with bronchial dysplasia. J Natl Cancer Inst 2002;94:1001–1009.PubMedGoogle Scholar
  84. 84.
    Ben-Mahdi MH, Gozin A, Driss F, et al. Anethole dithiolethione regulates oxidant-induced tyrosine kinase activation in endothelial cells. Antioxid Redox Signal 2000;2:789–799.PubMedGoogle Scholar
  85. 85.
    Le Ferrec E, Lagadic-Grossmann D, Rauch C, et al. Transcriptional induction of CYP 1 A 1 by oltipraz in human Caco-2 cells is aryl hydrocarbon receptor- and calciumdependent. J Biol Chem 2002;277:24,780–24,787.Google Scholar
  86. 86.
    Maxiutenko YY, Curphey TJ, Libby AH, et al. Identification of dithiolethiones with better chemopreventive properties than oltipraz. Carcinogenesis 1998;19:1609–1615.Google Scholar
  87. 87.
    Prochaska HJ, Santamaria AB, Talalay P. Rapid detection of inducers of enzymes that protect against carcinogens. Proc Natl Acad Sci USA 1992;89:2394–2398.PubMedGoogle Scholar
  88. 88.
    Zhang Y, Talalay P, Cho C-G, Posner GH. A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure. Proc Nall Acad Sci USA 1992;89:2399–2403.Google Scholar
  89. 89.
    Pezzutto JM. Plant-derived anticancer agents. Biochem Pharmacol 1997;53:121–133.Google Scholar
  90. 90.
    Talalay P, Talalay P. The importance of using scientific principles in the development of medicinal agents from plants. Acad Med 2001;76:238–247.PubMedGoogle Scholar
  91. 91.
    Block G, Patterson B, Subar A. Fruit, vegetables and cancer prevention: a review of the epidemiological evidence. Nutr Cancer 1992;18:1–29.PubMedGoogle Scholar
  92. 92.
    Steinmetz KA, Potter JD. Vegetables, fruit, and cancer. I. Epidemiology. Cancer Causes Control 1991;2:325–357.PubMedGoogle Scholar
  93. 93.
    Steinmetz KA, Potter JD. Vegetables, fruit, and cancer prevention: a review. J Am Diet Assoc 1996;96:1027–1039.PubMedGoogle Scholar
  94. 94.
    World Cancer Research Fund. Food, Nutrition and the Prevention of Cancer: A Global Perspective. American Institute for Cancer Research, Washington, DC, 1997Google Scholar
  95. 95.
    Beecher CWW. Cancer preventive properties of varieties of Brassica oleracea: a review. Am J Clin Nutr 1994;59 Suppl: 1165–1170.Google Scholar
  96. 96.
    Talalay P, Fahey JW. Phytochemicals from cruciferous plants protect against cancer by modulating carcinogen metabolism. J Nutr 2001;131:3027S-3033S.PubMedGoogle Scholar
  97. 97.
    Steinmetz KA, Potter, JD. Vegetables, fruit, and cancer. II. Mechanisms. Cancer Causes Control 1991;2:427–442.PubMedGoogle Scholar
  98. 98.
    Kolonel LN, Hankin JH, Whittemore AS, et al. Vegetables, fruits, legumes and prostate cancer: a multicenter case-control study. Cancer Epidemiol Biomarkers Prey 2000;9:795–804.Google Scholar
  99. 99.
    Cohen JH, Kristal AR, Stanford JL. Fruit and vegetable intake and prostate cancer risk. J Natl Cancer Inst 2000;92: 61–68.PubMedGoogle Scholar
  100. 100.
    Terry P, Wolk A, Persson, I. Magnusson C. Brassica vegetables and breast cancer risk. J Am Med Assoc 2001;286:2975–2977.Google Scholar
  101. 101.
    Zhang SM, Hunter DJ, Rosner BA, et al. Intake of fruits, vegetables, and related nutrients and the risk of nonHodgkin’s lymphoma among women. Cancer Epidemiol Biomarkers Prey 2000;9:477–485.Google Scholar
  102. 102.
    Michaud DS, Spiegelman D, Clinton SK, et al. Fruit and vegetable intake and incidence of bladder cancer in a male prospective cohort. J Natl Cancer Inst 1999;91:605–613.PubMedGoogle Scholar
  103. 103.
    Fahey JW, Zalcmann A, Talalay P. The chemical diversity and distribution of glucosinolates and isothiocyanates among plants. Phytochemistry 2001;56:5–51.PubMedGoogle Scholar
  104. 104.
    Zhang Y, Talalay P. Anticarcinogenic activities of organic isothiocyanates: chemistry and mechanisms. Cancer Res (Suppl) 1994;54:1976s-1981s.PubMedGoogle Scholar
  105. 105.
    Hecht SS. Chemoprevention by isothiocyanates. J Cell Biochem (Suppl) 1995;22:195–209.Google Scholar
  106. 106.
    Hecht SS. Chemoprevention by modifiers of carcinogen metabolism, In Phytochemicals as Bioactive Agents. Bidlack WR, Omaye ST, Meskin MS, Topham DKW, eds. Technomic Publishing Co., Lancaster, PA, 2000; pp. 43–74.Google Scholar
  107. 107.
    Boogards JJP, Verhagen H, Willems MI, et al. Consumption of Brussels sprouts results in elevated alpha-class glutathione S-transferase levels in human blood plasma. Carcinogenesis 1994;15:1073–1075.Google Scholar
  108. 108.
    Nijhoff WA, Grubben MJAL, Nagengast FM, et al. Effects of consumption of Brussels sprouts on intestinal and lymphocytic glutathione S-transferases in humans. Carcinogenesis 1995;16:2125–2128.PubMedGoogle Scholar
  109. 109.
    Clapper ML, Szarka CE, Pfeiffer GR, et al. Preclinical and clinical evaluation of broccoli supplements as inducers of glutathione S-transferase activity. Clin Cancer Res 1997;3:25–30.PubMedGoogle Scholar
  110. 110.
    Conney AH, Pantuck EJ, Hsiao K-C, et al. Enhanced phenacetin metabolism in human subjects fed charcoalbroiled beef. Clin Pharmacol Ther 1976:20:633–643.PubMedGoogle Scholar
  111. 111.
    Conney AH, Pantuck EJ, Hsiao KC, et al. Regulation of drug metabolism in man by environmental chemicals and diet. Fed Proc 1977;36:1647–1652.PubMedGoogle Scholar
  112. 112.
    Conney AH, Buening NM, Pantuck EJ, et al. Regulation of human drug metabolism by dietary factors. CIBA Found Symp 1980;76:147–167.Google Scholar
  113. 113.
    Prochaska HJ, Santamaria AB. Direct measurement of NAD(P)H: quinone reductase from cells in cultured microtiter wells: a screening assay for anticarcinogenic enzyme inducers. Anal Biochem 1988;169:328–336.PubMedGoogle Scholar
  114. 114.
    Prochaska HJ, Santamaria AB, Talalay P. Rapid detection of inducers of enzymes that protect against cancer. Proc Natl Acad Sci USA 1992;89:2394–2398.PubMedGoogle Scholar
  115. 115.
    Fahey JW, Zhang Y, Talalay P. Broccoli sprouts: an exceptionally rich source of inducers of enzymes that protect against chemical carcinogens. Proc Natl Acad Sci USA 1997;94:10,367–10,372.PubMedGoogle Scholar
  116. 116.
    Zhang Y, Talalay P, Cho CG, Posner GH. A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure. Proc Natl Acad Sci USA 1992;89:2399–2403.PubMedGoogle Scholar
  117. 117.
    Zhang Y, Kensler TW, Cho CG, et al. Anticarcinogenic activities of sulforaphane and structurally related synthetic norbornyl isothiocyanates. Proc Natl Acad Sci USA 1994;91:3147–3150.PubMedGoogle Scholar
  118. 118.
    Gerhauser C, You M, Liu J, et al. Cancer chemopreventive potential of sulforamate, a novel analog of sulforaphane that induces phase 2 drug-metabolizing enzymes. Cancer Res 1997;57:272–278.PubMedGoogle Scholar
  119. 119.
    Singletary K, MacDonald C. Inhibition of benzo[a]pyreneand 1,6-dinitropyrene-DNA adduct formation in human mammary epithelial cells by dibenzoylmethane and sulforaphane. Cancer Lett 2000;155: 47–54.PubMedGoogle Scholar
  120. 120.
    Chung FL, Conaway CC, Rao CV, Reddy BS. Chemoprevention of colonic aberrant crypt foci in Fischer rats by sulforaphane and phenethyl isothiocyanate. Carcinogenesis 2000;21:2287–2291.PubMedGoogle Scholar
  121. 121.
    Zhang Y, Talalay P. Mechanisms of differential potencies of isothiocyanates as inducers of anticarcinogenic phase 2 enzymes. Cancer Res 1998;58:4632–4639.PubMedGoogle Scholar
  122. 122.
    Zhang Y, Talalay P. Role of glutathione in the accumulation of anticarcinogenic isothiocyanates and their glutathione conjugates in murine hepatoma cells. Carcinogenesis 2000;21:1175–1182.PubMedGoogle Scholar
  123. 123.
    Zhang Y. Molecular mechanism of rapid cellular accumulation of anticarcinogenic isothiocyanates. Carcinogenesis 2001;22:425–431.PubMedGoogle Scholar
  124. 124.
    Zhang Y, Callaway EC. High cellular accumulation of sulforaphane, a dietary anticarcinogen, is followed by rapid transporter-mediated export as a glutathione conjugate. Biochem J 2002;365:301–307.Google Scholar
  125. 125.
    Conaway CC, Krzeminsik J, Amin S, Chung FL. Decomposition rates of isothiocyanate conjugates determine their activity as inhibitors of cytochrome P450 enzymes. Chem Res Toxicol 2002;14:1170–1176.Google Scholar
  126. 126.
    Chiao JW, Chung FL, Kancheria R, et al. Sulforaphane and its metabolite mediate growth arrest and apoptosis in human prostate cancer cells. Int J Oncol 2002;20:631–636.PubMedGoogle Scholar
  127. 127.
    Fimognari C, Nusse M, Cesari R, et al. Growth inhibition, cell-cycle arrest and apoptosis in human T- cell leukemia by the isothiocyanate sulforaphane. Carcinogenesis 2002;23:581–586.PubMedGoogle Scholar
  128. 128.
    Gamet-Payrastre L, Li P, Lumeau S, et al. Sulforaphane, a naturally occurring isothiocyanate, induces cell cycle arrest and apoptosis in HT29 human colon cancer cells. Cancer Res 2000;60:1426–1433.PubMedGoogle Scholar
  129. 129.
    Prestera T, Fahey JW, Holtzclaw WD, et al. Comprehensive chromatographic and spectroscopic methods for the separation and identification of intact glucosinolates. Anal Biochem 1996;239:168–179.PubMedGoogle Scholar
  130. 130.
    Troyer JK, Stephenson KK, Fahey JW. Analysis of glucosinolates from broccoli and other cruciferous vegetables by hydrophilic interaction liquid chromatography. J Clin Chromatography 2001;919:299–304.Google Scholar
  131. 131.
    Chung F-L, Morse MA, Elklind KI, Lewis J. Quantitation of human uptake of the anticarcinogen phenethyl isothiocyanate after a watercress meal. Cancer Epidemiol Biomark Prey 1992;1:383–388.Google Scholar
  132. 132.
    Jiao D, Ho CT, Foiles P, Chung FL. Identification and quantitation of the N-acetylcysteine conjugate of allyl isothiocyanate in human urine after ingestion of mustard. Cancer Epidemiol Biomark Prey 1994;3:487–492.Google Scholar
  133. 133.
    Mennicke WH, Görler K, Krumbiegel G, et al. Studies on the metabolism and excretion of benzyl isothiocyanate in man. Xenobiotica 1988;4:441–447.Google Scholar
  134. 134.
    Brüsewitz G, Cameron BD, Chasseaud LF, et al. The metabolism of benzyl isothiocyanate and its cysteine conjugate. Biochem J 1977;162:99–107.PubMedGoogle Scholar
  135. 135.
    Zhang Y, Cho C-G, Posner GH, Talalay P. Spectroscopic quantitation of organic isothiocyanates by cyclocondensation with vicinal dithiols. Anal Biochem 1992;205:100–107.PubMedGoogle Scholar
  136. 136.
    Zhang Y, Wade KL, Prestera T, Talalay P. Quantitative determination of isothiocyanates, dithiocarbamates, carbon disulfide, and related thiocarbonyl compounds by cyclocondensation with 1,2-benzenedithiol. Anal Biochem 1996;239:160–167.PubMedGoogle Scholar
  137. 137.
    Shapiro TA, Fahey JW, Wade KL, et al. Human metabolism and excretion of cancer chemoprotective glucosinolates and isothiocyanates of cruciferous vegetables. Cancer Epidemiol Biomark Prey 1998;7:1091–1100.Google Scholar
  138. 138.
    Shapiro TA, Fahey JW, Wade KL, et al. Chemoprotective glucosinolates and isothiocyanates of broccoli sprouts: metabolism and excretion in humans. Cancer Epidemiol Biomark Prey 2001;10:501–508.Google Scholar
  139. 139.
    Ye L, Dinkova-Kostova AT, Wade KL, et al. Quantitative determination of dithiolecarbamates in human plasma, serum, erythrocytes and urine: pharmacokinetics of broccoli sprout isothiocyanates in humans. Clin Chim Acta 2002;316:43–53.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2004

Authors and Affiliations

  • Thomas W. Kensler
  • Paul Talalay

There are no affiliations available

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