2: Drug Metabol Drug Interact 2000;17(1-4):3-22 Chemoprotection by organosulfur inducers of phase 2 enzymes: dithiolethiones and dithiins. Kensler TW, Curphey TJ, Maxiutenko Y, Roebuck BD. Department of Environmental Health Sciences, Johns Hopkins School of Hygiene and Public Health, Baltimore, MD 21205, USA. tkensler@jhsph.edu One of the major mechanisms of protection against carcinogenesis, mutagenesis, and other forms of toxicity mediated by carcinogens is the induction of enzymes involved in their metabolism, particularly phase 2 enzymes such as glutathione S-transferases, UDP-glucuronosyl transferases, and quinone reductases. Animal studies indicate that induction of phase 2 enzymes is a sufficient condition for obtaining chemoprevention and can be achieved by administering any of a diverse array of naturally-occurring and synthetic chemopreventive agents. Alliaceous and cruciferous plants are rich in organosulfur compounds with inducer activity. Indeed, monitoring of enzyme induction has led to the recognition or isolation of novel, potent chemopreventive agents such as 1,2-dithiole-3-thiones, dithiins and the isothiocyanate sulforaphane. For example, oltipraz, a substituted 1,2-dithiole-3-thione originally developed as an antischistosomal agent, possesses chemopreventive activity against different classes of carcinogens targeting multiple organs. Mechanistic studies in rodent models for chemoprevention of aflatoxin B1 (AFB1)-induced hepatocarcinogenesis by oltipraz indicates that increased expression of phase 2 genes is of central importance, although inhibition of phase 1 activation of aflatoxin B1 can also contribute to protection. Exposure of rodents to 1,2-dithiole-3-thiones triggers nuclear accumulation of the transcription factor Nrf2 and its enhanced binding to the Antioxidant Response Element, leading to transcriptional activation of a score of genes involved in carcinogen detoxification and attenuation of oxidative stress. Nrf2-deficient mice fail to induce many of these genes in response to oltipraz and the impact of this genotype on the chemopreventive efficacy of dithiolethiones is currently under investigation. To test the hypothesis that enzyme induction is a useful strategy for chemoprevention in humans, three key elements are necessary: a candidate agent, an at-risk population and modulatable intermediate endpoints. Towards this end, a placebo-controlled, double blind clinical trial of oltipraz was conducted in residents of Qidong, P.R. China who are exposed to dietary aflatoxins and who are at high risk for the development of liver cancer. Oltipraz significantly enhanced excretion of a phase 2 product, aflatoxin-mercapturic acid, a derivative of the aflatoxin-glutathione conjugate, in the urine of study participants administered 125 mg oltipraz by mouth daily. Administration of 500 mg oltipraz once a week led to a significant reduction in the excretion of the primary oxidative metabolite of AFB1, aflatoxin M1, when measured shortly after drug administration. While this study highlighted the general feasibility of inducing phase 2 enzymes in humans, a longer term intervention is addressing whether protective alterations in aflatoxin metabolism can be sustained for extended periods of time in this high-risk population. Food-based approaches to chemoprotection, targeted both to the general population and high-risk individuals, offer many practical advantages compared to the use of pharmaceutical agents. Thus, identification and utilization of naturally-occurring organosulfur chemoprotectors including dithiins should be a high priority. Publication Types: Review Review, tutorial PMID: 11201301 [PubMed - indexed for MEDLINE]
3: Carcinogenesis 2000 Jun;21(6):1175-82 Role of glutathione in the accumulation of anticarcinogenic isothiocyanates and their glutathione conjugates by murine hepatoma cells. Zhang Y. Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. yzhang@jhmi.edu Isothiocyanates (ITCs) are abundant in the human diet. Many potently inhibit tumorigenesis induced by a wide variety of chemical carcinogens in rodents. Recently, we observed that several ITCs accumulated to very high concentrations in cultured cells and that their accumulated levels were closely related to their potencies in inducing phase II enzymes [NAD(P)H:quinone reductase and glutathione transferases] that detoxify carcinogens. To elucidate the molecular mechanism responsible for this accumulation, the intracellular chemical identities of two ITCs, sulforaphane [SF, 1-isothiocyanato-(4R,S)-(methylsulfinyl)butane] and benzyl-ITC, were investigated in murine hepatoma cells. Both ITCs accumulated very rapidly to high intracellular concentrations, but, remarkably, most of the intracellular forms of the ITCs were dithiocarbamates resulting from conjugation with reduced glutathione (GSH). For example, the intracellular concentration reached 6.4 mM when cells were exposed to 100 microM SF for 30 min at 37 degrees C and 95% of the accumulated product was the GSH conjugate. Cellular accumulation of each ITC was accompanied by a profound reduction in cellular GSH levels. These findings, together with our previous observation that accumulation of ITCs depended on cellular GSH levels, strongly suggest that intracellular conjugation of ITCs with GSH is mainly responsible for ITC accumulation. Surprisingly, rapid accumulation to high concentrations also occurred when cells were exposed to the GSH-ITC conjugates. However, these conjugates were apparently not absorbed intact, but were hydrolyzed extracellularly to free ITCs that were taken up by the cells. This conclusion is supported by the finding that suppression of dissociation of the conjugates by excess GSH or other thiols blocks accumulation of the conjugates. PMID: 10837007 [PubMed - indexed for MEDLINE]
4: Adv Exp Med Biol 1999;472:207-21 Phytochemicals as modulators of cancer risk. Bradlow HL, Telang NT, Sepkovic DW, Osborne MP. Strang Cancer Research Laboratory, New York, NY 10021, USA. These results, describing antitumor activity of some of the phytochemicals that have been actively studied, suggest that dietary changes could play a role in decreasing the incidence of a variety of tumors. 13C and the other compounds discussed may well be only prototypes for other as yet unexplored phytochemicals present in the diet. There have been no attempts to explore the possibilities of synergistic action among the various phytochemicals, 13C, limonene, curcumin, epigallocatechin gallate, sulforaphene, or genistein. Mixtures of these compounds might well show potency at lower doses for each of the compounds and show even greater promise than that already demonstrated. Publication Types: Review Review, tutorial PMID: 10736628 [PubMed - indexed for MEDLINE]
5: Cancer Res 2000 Mar 1;60(5):1426-33 Sulforaphane, a naturally occurring isothiocyanate, induces cell cycle arrest and apoptosis in HT29 human colon cancer cells. Gamet-Payrastre L, Li P, Lumeau S, Cassar G, Dupont MA, Chevolleau S, Gasc N, Tulliez J, Terce F. INRA, Laboratoire des Xenobiotiques, Toulouse, France. Sulforaphane is an isothiocyanate that is present naturally in widely consumed vegetables and has a particularly high concentration in broccoli. This compound has been shown to block the formation of tumors initiated by chemicals in the rat. Although sulforaphane has been proposed to modulate the metabolism of carcinogens, its mechanism of action remains poorly understood. We have previously demonstrated that sulforaphane inhibits the reinitiation of growth and decreases the cellular viability of quiescent human colon carcinoma cells (HT29). Moreover, the weak effect observed on differentiated CaCo2 cells suggests a specific anticancer activity for this compound. Here we investigated the effect of sulforaphane on the growth and viability of HT29 cells during their exponentially growing phase. We observed that sulforaphane induced a cell cycle arrest in a dose-dependent manner, followed by cell death. This sulforaphane-induced cell cycle arrest was correlated with an increased expression of cyclins A and B1. Moreover, we clearly demonstrated that sulforaphane induced cell death via an apoptotic process. Indeed, a large proportion of treated cells display the following: (a) translocation of phosphatidylserine from the inner layer to the outer layer of the plasma membrane; (b) typical chromatin condensation; and (c) ultrastructural modifications related to apoptotic cell death. We also showed that the expression of p53 was not changed in sulforaphane-treated cells. In contrast, whereas bcl-2 was not detected, we observed increased expression of the proapoptotic protein bax, the release of cytochrome c from the mitochondria to the cytosol, and the proteolytic cleavage of poly(ADP-ribose) polymerase. In conclusion, our results strongly suggest that in addition to the activation of detoxifying enzymes, induction of apoptosis is also involved in the sulforaphane-associated chemoprevention of cancer. PMID: 10728709 [PubMed - indexed for MEDLINE]
6: J Nutr 2000 Feb;130(2S Suppl):467S-471S Progress in cancer chemoprevention: development of diet-derived chemopreventive agents. Kelloff GJ, Crowell JA, Steele VE, Lubet RA, Malone WA, Boone CW, Kopelovich L, Hawk ET, Lieberman R, Lawrence JA, Ali I, Viner JL, Sigman CC. National Cancer Institute, Division of Cancer Prevention, Bethesda, MD 20892, USA. Because of their safety and the fact that they are not perceived as "medicine," food-derived products are highly interesting for development as chemopreventive agents that may find widespread, long-term use in populations at normal risk. Numerous diet-derived agents are included among the >40 promising agents and agent combinations that are being evaluated clinically as chemopreventive agents for major cancer targets including breast, prostate, colon and lung. Examples include green and black tea polyphenols, soy isoflavones, Bowman-Birk soy protease inhibitor, curcumin, phenethyl isothiocyanate, sulforaphane, lycopene, indole-3-carbinol, perillyl alcohol, vitamin D, vitamin E, selenium and calcium. Many food-derived agents are extracts, containing multiple compounds or classes of compounds. For developing such agents, the National Cancer Institute (NCI) has advocated codevelopment of a single or a few putative active compounds that are contained in the food-derived agent. The active compounds provide mechanistic and pharmacologic data that may be used to characterize the chemopreventive potential of the extract, and these compounds may find use as chemopreventives in higher risk subjects (patients with precancers or previous cancers). Other critical aspects to developing the food-derived products are careful analysis and definition of the extract to ensure reproducibility (e.g., growth conditions, chromatographic characteristics or composition), and basic science studies to confirm epidemiologic findings associating the food product with cancer prevention. Publication Types: Review Review, tutorial PMID: 10721931 [PubMed - indexed for MEDLINE]
7: Ann N Y Acad Sci 1999;889:1-13 Progress in cancer chemoprevention. Kelloff GJ, Crowell JA, Steele VE, Lubet RA, Boone CW, Malone WA, Hawk ET, Lieberman R, Lawrence JA, Kopelovich L, Ali I, Viner JL, Sigman CC. National Cancer Institute, Division of Cancer Prevention, Bethesda, Maryland 20892, USA. kelloffg@dcpcepn.nci.nih.gov More than 40 promising agents and agent combinations are being evaluated clinically as chemopreventive drugs for major cancer targets. A few have been in vanguard, large-scale intervention trials--for example, the studies of tamoxifen and fenretinide in breast, 13-cis-retinoic acid in head and neck, vitamin E and selenium in prostate, and calcium in colon. These and other agents are currently in phase II chemoprevention trials to establish the scope of their chemopreventive efficacy and to develop intermediate biomarkers as surrogate end points for cancer incidence in future studies. In this group are fenretinide, 2-difluoromethylornithine, and oltipraz. Nonsteroidal anti-inflammatories (NSAID) are also in this group because of their colon cancer chemopreventive effects in clinical intervention, epidemiological, and animal studies. New agents are continually considered for development as chemopreventive drugs. Preventive strategies with antiandrogens are evolving for prostate cancer. Anti-inflammatories that selectively inhibit inducible cyclooxygenase (COX)-2 are being investigated in colon as alternatives to the NSAID, which inhibit both COX-1 and COX-2 and derive their toxicity from COX-1 inhibition. Newer retinoids with reduced toxicity, increased efficacy, or both (e.g., 9-cis-retinoic acid) are being investigated. Promising chemopreventive drugs are also being developed from dietary substances (e.g., green and black tea polyphenols, soy isoflavones, curcumin, phenethyl isothiocyanate, sulforaphane, lycopene, indole-3-carbinol, perillyl alcohol). Basic and translational research necessary to progress in chemopreventive agent development includes, for example, (1) molecular and genomic biomarkers that can be used for risk assessment and as surrogate end points in clinical studies, (2) animal carcinogenesis models that mimic human disease (including transgenic and gene knockout mice), and (3) novel agent treatment regimens (e.g., local delivery to cancer targets, agent combinations, and pharmacodynamically guided dosing). Publication Types: Review Review, tutorial PMID: 10668477 [PubMed - indexed for MEDLINE]
3: Biochem Pharmacol 2000 Jul 15;60(2):221-31 Studies on the mechanism of the inhibition of human leukaemia cell growth by dietary isothiocyanates and their cysteine adducts in vitro. Xu K, Thornalley PJ. Department of Biological Sciences, University of Essex, Central Campus, Wivenhoe Park, CO4 3SQ, Essex, Colchester, UK. The dietary isothiocyanates and cancer chemopreventive agents phenethyl isothiocyanate and allyl isothiocyanate and their cysteine conjugates inhibited the growth and induced apoptosis of human leukaemia HL60 (p53-) and human myeloblastic leukaemia-1 cells (p53+) in vitro. The median growth inhibitory concentration (GC(50)) values were in the range 1.49-3.22 microM in cultures with 10% serum. Isothiocyanates and cysteine conjugates had increased potency against HL60 cells in serum-free medium, with GC(50) values of 0.8-0. 9 microM. The potency of the compounds decreased with increased serum content of the medium, but that of the cysteine conjugates decreased more markedly. Growth inhibition and toxicity was characterised by either a rapid interaction of the isothiocyanate with the cells in the first hour of culture or exposure to isothiocyanate liberated from the cysteine conjugate in the initial 3 hr of culture, inhibition of macromolecule synthesis, and a commitment to apoptosis which developed in the initial 24 hr. Activities of caspase-3 and caspase-8 were increased during isothiocyanate-induced apoptosis, but caspase-1 activity was not. The general caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone and the specific caspase-8 inhibitor N-benzyloxycarbonyl-Ile-Glu(OMe)-Thr-Asp(OMe)-fluoromethylketone inhibited apoptosis, but specific caspase-1 and caspase-3 inhibitors did not. The antiproliferative activities were limited by hydrolysis of the isothiocyanate. This suggests that caspase-8 has a critical role, and caspase-3 a supporting role, in isothiocyanate-induced apoptosis in which p53 is not an obligatory participant. Isothiocyanate-induced apoptosis may suppress the growth of preclinical tumours and contribute to the well-established decreased cancer incidence associated with a vegetable-rich diet. PMID: 10825467 [PubMed - indexed for MEDLINE]
4: Adv Exp Med Biol 1999;472:159-68 Brassica vegetables and cancer prevention. Epidemiology and mechanisms. van Poppel G, Verhoeven DT, Verhagen H, Goldbohm RA. TNO Nutrition and Food Research Institute, Zeist, The Netherlands. This paper first gives an overview of the epidemiological data concerning the cancer-preventive effect of brassica vegetables, including cabbages, kale, broccoli, Brussels sprouts, and cauliflower. A protective effect of brassicas against cancer may be plausible due to their relatively high content of glucosinolates. Certain hydrolysis products of glucosinolates have shown anticarcinogenic properties. The results of six cohort studies and 74 case-control studies on the association between brassica consumption and cancer risk are summarized. The cohort studies showed inverse associations between the consumption of brassica's and risk of lung cancer, stomach cancer, all cancers taken together. Of the case-control studies 64% showed an inverse association between consumption of one or more brassica vegetables and risk of cancer at various sites. Although the measured effects might have been distorted by various types of bias, it is concluded that a high consumption of brassica vegetables is associated with a decreased risk of cancer. This association appears to be most consistent for lung, stomach, colon and rectal cancer, and least consistent for prostatic, endometrial and ovarian cancer. It is not yet possible to resolve whether associations are to be attributed to brassica vegetables per se or to vegetables in general. Further epidemiological research should separate the anticarcinogenic effect of brassica vegetables from the effect of vegetables in general. The mechanisms by which brassica vegetables might decrease the risk of cancer are reviewed in the second part of this paper. Brassicas, including all types of cabbages, broccoli, cauliflower, and Brussels sprouts, may be protective against cancer due to their glucosinolate content. Glucosinolates are usually broken down through hydrolysis catalysed by myrosinase, an enzyme that is released from damaged plant cells. Some of the hydrolysis products, viz. indoles, and isothiocyanates, are able to influence phase 1 and phase 2 biotransformation enzyme activities, thereby possibly influencing several processes related to chemical carcinogenesis, e.g. the metabolism, DNA-binding, and mutagenic activity of promutagens. Most evidence concerning anticarcinogenic effects of glucosinolate hydrolysis products and brassica vegetables has come from studies in animals. In addition, studies carried out in humans using high but still realistic human consumption levels of indoles and brassica vegetables have shown putative positive effects on health. The combination of epidemiological and experimental data provide suggestive evidence for a cancer preventive effect of a high intake of brassica vegetables. Publication Types: Review Review, tutorial PMID: 10736624 [PubMed - indexed for MEDLINE]
5: J Nutr 1999 Mar;129(3):768S-774S Chemoprevention of cancer by isothiocyanates, modifiers of carcinogen metabolism. Hecht SS. University of Minnesota Cancer Center, Minneapolis, MN 55455, USA. Substantial quantities of isothiocyanates are released upon consumption of normal amounts of a number of cruciferous vegetables. Some of these naturally occurring isothiocyanates such as phenethyl isothiocyanate (PEITC), benzyl isothiocyanate (BITC) and sulforaphane are effective inhibitors of cancer induction in rodents treated with carcinogens. A large amount of data demonstrate that isothiocyanates act as cancer chemopreventive agents by favorably modifying carcinogen metabolism via inhibition of Phase 1 enzymes and/or induction of Phase 2 enzymes. These effects are quite specific, depending on the structure of the isothiocyanate and carcinogen. One of the most thoroughly studied examples of isothiocyanate inhibition of rodent carcinogenesis is inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis by PEITC. This occurs because PEITC blocks the metabolic activation of NNK, resulting in increased urinary excretion of detoxified metabolites. Similar effects on NNK metabolism have been observed in smokers who consumed watercress, a source of PEITC. On the basis of these observations and knowledge of the carcinogenic constituents of cigarette smoke, a strategy for chemoprevention of lung cancer can be developed. Publication Types: Review Review, tutorial PMID: 10082787 [PubMed - indexed for MEDLINE]
6: Int J Mol Med 1998 Apr;1(4):747-53 Effect of dietary phytochemicals on cancer development (review) Waladkhani AR, Clemens MR. Medizinische Abteilung I, Krankenanstalt Mutterhaus der Borromaerinnen, 54219 Trier, Germany. Vegetables, fruits, and whole grains contain a wide variety of phytochemicals that have the potential to modulate cancer development. There are many biologically plausible reasons why consumption of plant foods might slow or prevent the appearance of cancer. These include the presence in plant foods of such potentially anticarcinogenic substances as carotenoids, chlorophyll, flavonoids, indole, isothiocyanate, polyphenolic compounds, protease inhibitors, sulfides, and terpens. The specific mechanisms of action of most phytochemicals in cancer prevention are not yet clear but appear to be varied. Considering the large number and variety of dietary phytochemicals, their interactive effects on cancer risk may be extremely difficult to assess. Phytochemicals can inhibit carcinogenesis by inhibiting phase I enzymes, and induction of phase II enzymes, scavenge DNA reactive agents, suppress the abnormal proliferation of early, preneoplastic lesions, and inhibit certain properties of the cancer cell. Publication Types: Review Review, tutorial PMID: 9852292 [PubMed - indexed for MEDLINE]
7: J Cell Biochem Suppl 1997;27:76-85 Chemopreventive potential of thiol conjugates of isothiocyanates for lung cancer and a urinary biomarker of dietary isothiocyanates. Chung FL, Jiao D, Conaway CC, Smith TJ, Yang CS, Yu MC. Division of Carcinogenesis and Molecular Epidemiology, American Health Foundation, Valhalla, New York 10595, USA. Natural and synthetic isothiocyanates (ITCs) are versatile chemopreventive agents in many animal systems. We have shown that phenethyl ITC (PEITC) and 6-phenylhexyl ITC (PHITC) are potent inhibitors against lung tumorigenesis induced by tobacco nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in both mouse and rat. The mechanism by which these ITCs inhibited lung tumorigenesis is attributed to their ability to decrease cytochrome P450 (P450) enzyme activities involved in the activation of NNK. Recently, we have found that thiol conjugates of ITCs inhibit P450 enzymes and are effective inhibitors of lung tumorigenesis. This is significant because conjugation with cellular thiols is the major route of ITC metabolism via the mercapturic acid pathway in rodents and humans. The thiol conjugates are less pungent and potentially less toxic, and they are more soluble and chemically less reactive than ITCs. These properties raise the prospect of substituting thiol conjugates for ITCs as chemopreventive agents. Furthermore, although ample rodent studies have established that ITCs inhibit tumorigenesis, the protective role of dietary ITCs against human cancers has not yet been established. As a prerequisite for such human studies, we have developed an HPLC-based assay, based on the condensation reaction of ITCs or conjugates with 1,2-benzenedithiol, for measuring a cyclocondensation product in human urine as an uptake biomarker of total ITCs. This assay was validated using urine samples from subjects who had ingested a known amount of watercress or mustard in a controlled diet. The assay is convenient and rapid, showing promise for analyzing urine samples obtained from population-based studies. Results from two such studies are presented to illustrate the potential application of this biomarker in epidemiologic studies. PMID: 9591196 [PubMed - indexed for MEDLINE]
8: Cancer Epidemiol Biomarkers Prev 1998 Feb;7(2):103-8 A urinary biomarker for uptake of dietary isothiocyanates in humans. Chung FL, Jiao D, Getahun SM, Yu MC. Division of Carcinogenesis and Molecular Epidemiology, American Health Foundation, Valhalla, New York 10595, USA. Isothiocyanates (ITCs) are a family of biologically active compounds that are distributed widely in cruciferous vegetables. Although studies in rodents have shown that these compounds are effective and versatile inhibitors of tumorigenesis, the role of dietary ITCs in the protection against human cancers remains to be established. A prerequisite of human studies is to develop an uptake biomarker for dietary ITCs. In this study, we describe a rapid high-performance liquid chromatography-based assay to measure the total ITC level in human urine. This assay is based on a previously described reaction of ITCs or their thiol conjugates with 1,2-benzenedithiol to yield a cyclocondensation product, 1,3-benzodithiole-2-thione, which then can be quantified by reverse phase high-performance liquid chromatography with UV detection. This new assay was validated by analyzing urine samples from 14 subjects who had consumed a known amount of watercress or brown mustard in a controlled experiment. The N-acetylcysteine conjugates of phenethyl ITC and allyl ITC from watercress and brown mustard, respectively, were quantified and compared with the results obtained from the current assay. Results of the two methods were highly correlated (r = 0.978), indicating the specificity of this new assay for dietary ITCs. The feasibility of this assay for population-based studies was examined using stored urine samples collected from nine participants of a prospective cohort study in Shanghai, China, who indicated that they were daily consumers of dark green vegetables. There was a 10-fold variation in urinary ITC contents among these samples, ranging from 0.7 to 7.0 micromol/g creatinine. These results show the potential use of this uptake biomarker in epidemiological studies to identify the role of dietary ITCs in modifying cancer risks in humans. PMID: 9488583 [PubMed - indexed for MEDLINE]
9: Proc Soc Exp Biol Med 1997 Nov;216(2):192-200 Detoxication enzymes and chemoprevention. Wilkinson J 4th, Clapper ML. Division of Population Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA. Detoxication enzymes protect cells from a wide variety of xenobiotics and endogenous toxins. Current data suggest that the balance between the Phase I carcinogen-activating enzymes and the Phase II detoxifying enzymes is critical to determining an individual's risk for cancer. Human deficiencies in Phase II enzyme activity, specifically glutathione-S-transferase (GST), have been identified and associated with increased risk for colon cancer. The increased frequency of the GST M1 null genotype among individuals with primarily smoking-related cancers has been documented. Induction of Phase II enzymes by naturally occurring or synthetic agents represents a promising strategy for cancer prevention. Both the required characteristics of potential chemopreventive agents and the role of the antioxidant response element in the monofunctional induction of Phase II enzymes have been discussed. The synthetic dithiolthione oltipraz induces a battery of Phase II enzymes and inhibits chemically induced tumors in a variety of target organs. Its ability to induce Phase II enzymes in human colon tissue and blood lymphocytes has been reported. Other promising inducers with chemopreventive activity include the isothiocyanates and polyphenols. These data collectively support the future development of Phase II enzyme inducers as clinical chemopreventive agents. Publication Types: Review Review, tutorial PMID: 9349688 [PubMed - indexed for MEDLINE]
10: Cancer Res 1998 Feb 1;58(3):402-8 Chemopreventive isothiocyanates induce apoptosis and caspase-3-like protease activity. Yu R, Mandlekar S, Harvey KJ, Ucker DS, Kong AN. Department of Pharmaceutics and Pharmacodynamics, Center for Pharmaceutical Biotechnology, College of Pharmacy, University of Illinois at Chicago, 60607-7173, USA. Isothiocyanates exert strong anticarcinogenic effects in a number of animal models of cancer, presumably by modulation of xenobiotic-metabolizing enzymes, such as by inhibition of cytochrome P-450 and/or by induction of phase II detoxifying enzymes. Here, we report that phenethyl isothiocyanate and other structurally related isothiocyanates, phenylmethyl isothiocyanate, phenylbutyl isothiocyanate, and phenylhexyl isothiocyanate, but not phenyl isothiocyanate induced apoptosis in HeLa cells in a time- and dose-dependent manner. Treatment with apoptosis-inducing concentrations of isothiocyanates also caused rapid and transient induction of caspase-3/CPP32-like activity. Furthermore, these isothiocyanates, except phenyl isothiocyanate, stimulated proteolytic cleavage of poly(ADP-ribose) polymerase, which followed the appearance of caspase activity and preceded DNA fragmentation. Pretreatment with a potent caspase-3 inhibitor acetyl-Asp-Glu-Val-Asp-aldehyde inhibited isothiocyanate-induced caspase-3-like activity and apoptosis. These results suggest that isothiocyanates may induce apoptosis through a caspase-3-dependent mechanism. The induction of apoptosis by isothiocyanates may provide a distinct mechanism for their chemopreventive functions. PMID: 9458080 [PubMed - indexed for MEDLINE]
11: Carcinogenesis 1997 Nov;18(11):2143-7 Chemopreventive activity of thiol conjugates of isothiocyanates for lung tumorigenesis. Jiao D, Smith TJ, Yang CS, Pittman B, Desai D, Amin S, Chung FL. Division of Carcinogenesis and Molecular Epidemiology, American Health Foundation, Valhalla, NY 10595, USA. A series of L-cysteine (L-Cys), glutathione (GSH), and N-acetyl-L-cysteine (NAC) conjugates of phenethyl (PEITC), benzyl (BITC), and 6-phenylhexyl isothiocyanate (PHITC) were studied for their inhibitory activity toward metabolic activation of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in mouse lung microsomes. Selected compounds, PEITC, PEITC-GSH, PEITC-NAC and PHITC-NAC, were also assayed for the potential chemopreventive activity toward NNK-induced lung tumorigenesis in A/J mice. Results showed that PEITC and its conjugates inhibited NNK metabolism with decreasing potency: PEITC < PEITC-GSH > PEITC-Cys > PEITC-NAC. PHITC and its GSH and NAC >conjugates exhibited nearly 10 times higher >inhibitory activity toward NNK metabolism than the >PEITC counterparts. In the tumor bioassay, as >expected, the conjugates exhibited inhibitory activity against lung tumorigenesis induced by NNK. >PEITC-GSH was not inhibitory at 4 micromol/mouse, but >it inhibited approximately 32% of lung tumor >multiplicity at 8 micromol/mouse. PEITC-NAC at 5 and >20 micromol/mouse both inhibited approximately 30% >tumor multiplicity. Among all the conjugates >examined, PHITC-NAC was the most potent. At a 5-micromol dose, it completely inhibited tumor >multiplicity and incidence to the background level >observed in the control group. These results revealed >that the structure-activity relationships of the conjugates are similar to those found with their >parent isothiocyanates (ITCs), i.e., the potency increased with the increasing alkyl chain length from two to six carbons in arylalkyl ITCs, suggesting that a common active species is involved. The inhibitory activity of ITC conjugates and the expected low toxicity make thiol conjugates of ITC a promising new series of chemopreventive agents. PMID: 9395214 [PubMed - indexed for MEDLINE]
12: Cancer Lett 1997 Mar 19;114(1-2):113-9 Isothiocyanates and plant polyphenols as inhibitors of lung and esophageal cancer. Stoner GD, Morse MA. Division of Environmental Health Sciences, The Ohio State University School of Public Health, Columbus 43210, USA. A group of arylalkyl isothiocyanates were tested for their abilities to inhibit tumorigenicity and DNA methylation induced by both the tobacco-specific nitrosamine, NNK, in A/J mouse lung and the esophageal-specific carcinogen, NMBA, in F344 rat esophagus. In addition, ellagic acid was tested for its ability to inhibit NMBA-induced esophageal tumorigenesis. In the strain A lung tumor model, PEITC effectively inhibited NNK-induced lung tumors at a dose of 5 micromol, but was not inhibitory at lower doses. PPITC, PBITC, PPeITC, and PHITC were all considerably more potent inhibitors of NNK lung tumorigenesis than PEITC, and PHITC was the most potent inhibitor of all. Thus, in the strain A lung tumor model, there was a trend of increased inhibitory efficacy among arylalkyl isothiocyanates with increased alkyl chain length. In the F344 rat esophageal tumor model, PPITC was clearly more potent than PEITC, BITC and PBITC had little inhibitory effect on esophageal tumorigenesis, and in a separate experiment, PHITC actually enhanced esophageal tumorigenesis. Thus, the structure-activity relationships for inhibition of tumorigenesis by arylalkyl isothiocyanates were considerably different in the two animal models. However, the effects of the isothiocyanates on tumorigenesis were well-correlated to their effects on DNA adduct formation in either model. The most likely mechanism of inhibition of tumorigenesis by these isothiocyanates is via inhibition of the cytochrome p450 enzymes responsible for activation of NNK in mouse lung or NMBA in rat esophagus. Ellagic acid was an effective inhibitor of esophageal tumorigenesis, although not as potent as PEITC or PPITC. Like the isothiocyanates, ellagic acid inhibits cytochrome p450-mediated activation of NMBA. PMID: 9103268 [PubMed - indexed for MEDLINE]
13: Chem Biol Interact 1997 Feb 28;103(2):79-129 A review of mechanisms underlying anticarcinogenicity by brassica vegetables. Verhoeven DT, Verhagen H, Goldbohm RA, van den Brandt PA, van Poppel G. TNO Nutrition and Food Research Institute, Zeist, The Netherlands. The mechanisms by which brassica vegetables might decrease the risk of cancer are reviewed in this paper. Brassicas, including all types of cabbages, broccoli, cauliflower and Brussels sprouts, may be protective against cancer due to their relatively high glucosinolate content. Glucosinolates are usually broken down through hydrolysis catalyzed by myrosinase, an enzyme that is released from damaged plant cells. Some of the hydrolysis products, viz. indoles and isothiocyanates, are able to influence phase 1 and phase 2 biotransformation enzyme activities, thereby possibly influencing several processes related to chemical carcinogenesis, e.g. the metabolism, DNA-binding and mutagenic activity of promutagens. A reducing effect on tumor formation has been shown in rats and mice. The anticarcinogenic action of isothiocyanates and indoles depends upon many factors, such as the test system, the target tissue, the type of carcinogen challenge and the anticarcinogenic compound, their dosage, as well as the timing of the treatment. Most evidence concerning anticarcinogenic effects of glucosinolate hydrolysis products and brassica vegetables has come from studies in animals. Animal studies are invaluable in identifying and testing potential anticarcinogens. In addition, studies carried out in humans using high but still realistic human consumption levels of indoles and brassica vegetables have shown putative positive effects on health. Publication Types: Review Review, tutorial PMID: 9055870 [PubMed - indexed for MEDLINE]
14: J Am Diet Assoc 1996 Oct;96(10):1027-39 Vegetables, fruit, and cancer prevention: a review. Steinmetz KA, Potter JD. World Cancer Research Fund, London, England. In this review of the scientific literature on the relationship between vegetable and fruit consumption and risk of cancer, results from 206 human epidemiologic studies and 22 animal studies are summarized. The evidence for a protective effect of greater vegetable and fruit consumption is consistent for cancers of the stomach, esophagus, lung, oral cavity and pharynx, endometrium, pancreas, and colon. The types of vegetables or fruit that most often appear to be protective against cancer are raw vegetables, followed by allium vegetables, carrots, green vegetables, cruciferous vegetables, and tomatoes. Substances present in vegetables and fruit that may help protect against cancer, and their mechanisms, are also briefly reviewed; these include dithiolthiones, isothiocyanates, indole-3-carbinol, allium compounds, isoflavones, protease inhibitors, saponins, phytosterols, inositol hexaphosphate, vitamin C, D-limonene, lutein, folic acid, beta carotene, lycopene, selenium, vitamin E, flavonoids, and dietary fiber. Current US vegetable and fruit intake, which averages about 3.4 servings per day, is discussed, as are possible noncancer-related effects of increased vegetable and fruit consumption, including benefits against cardiovascular disease, diabetes, stroke, obesity, diverticulosis, and cataracts. Suggestions for dietitians to use in counseling persons toward increasing vegetable and fruit intake are presented. Publication Types: Review Review, academic PMID: 8841165 [PubMed - indexed for MEDLINE]
15: IARC Sci Publ 1996;(139):61-90 Vegetables, fruit and phytoestrogens as preventive agents. Potter JD, Steinmetz K. Cancer Prevention Research Program, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. The practice of medicine-both past and present-often involves the prescription of specific foods (almost always plants) or their potent derivatives, to treat a wide spectrum of illnesses. Foods that have been ascribed healing properties include the Cruciferae, the allium family, celery, cucumber, endive, parsley, radish and legumes. Review of the epidemiological data, including both cohort and case-control studies, of all cancer sites strongly suggests that plant foods also have preventive potential and that consumption of the following groups and types of vegetables and fruits is lower in those who subsequently develop cancer: raw and fresh vegetables, leafy green vegetables, Cruciferae, carrots, broccoli, cabbage, lettuce, and raw and fresh fruit (including tomatoes and citrus fruit). Other data suggest that foods high in phytoestrogens, particularly soy (which contains isoflavones), or high in precursor compounds that can be metabolized by gut bacteria into active agents, particularly some grains and vegetables with woody stems (which contain precursors to lignans), are plausibly associated with a lower risk of sex-hormone-related cancers. The human evidence for these latter associations is not strong. There are many biologically plausible reasons why consumption of plant foods might slow or prevent the appearance of cancer. These include the presence in plant foods of such potentially anticarcinogenic substances as carotenoids, vitamin C, vitamin E, selenium, dietary fibre (and its components), dithiolthiones, isothiocyanates, indoles, phenols, protease inhibitors, allium compounds, plant sterols, and limonene. Phytoestrogens are also derived from some vegetables and berries as well as grains and seeds. Most of the data for the observations on the anticarcinogenic potential of all of these compounds have come from animal and in vitro studies. At almost every one of the stages of the cancer process, identified phytochemicals are known to be able to alter the likelihood of carcinogenesis-occasionally in a way that enhances risk but usually in a favourable direction. For example, glucosinolates and indoles, thiocyanates and isothiocyanates, phenols, and coumarins can induce a multiplicity of phase II (solubilizing and usually inactivating) enzymes; ascorbate and phenols block the formation of carcinogens such as nitrosamines; flavonoids and carotenoids act as antioxidants, essentially disabling the carcinogenic potential of specific compounds; lipid-soluble compounds such as carotenoids and sterols may alter membrane structure or integrity; some sulphur-containing compounds suppress DNA and protein synthesis; carotenoids can suppress DNA synthesis and enhance differentiation; and phytoestrogens compete with estradiol for estrogen receptors in a way that is generally antiproliferative. Consumption of diets low in plant foods results in a reduced intake of a wide variety of those substances that can plausibly lower cancer risk. In the presence of a diet and lifestyle high in potential carcinogens (whether derived from fungal contamination, cooking or tobacco) or high in promoters (such as salt and alcohol), overall risk of cancer at many epithelial sites is elevated. Plant foods appear to exert a general risk-lowering effect; the patterns of exposure to cancer initiators and promoters and of genetic susceptibility may determine the variations in the site-specific risks of cancer seen across populations. Publication Types: Review Review, tutorial PMID: 8923020 [PubMed - indexed for MEDLINE]
16: IARC Sci Publ 1996;(139):33-45 Micronutrients (vitamins and minerals) as cancer-preventive agents. Omenn GS. School of Public & Health Community Medicine, University of Washington, Seattle, USA. Reduction of incidence and mortality of common cancers requires successful preventive interventions both in high-risk populations and in the population at large. Agents chosen for intervention trials must have been demonstrated to have significant and plausible biological activity in animal, in vitro, and short-term human studies, and these should be supported by observational epidemiological analyses. This chapter reviews evidence about vitamins and minerals as possible cancer-protective agents, emphasizing carotenoids (notably beta-carotene), natural vitamin A, vitamin E, selenium, vitamin C, calcium, vitamin D and folic acid. It is helpful to group agents according to apparent primary mechanism of effect, such as antioxidant (and/or pro-oxidant) effects for beta-carotene, vitamin C, vitamin E, selenium, zinc, copper, iron, manganese, phenolic compounds and isothiocyanates. Certain conditions associated with increased concentrations of free radicals and reactive oxygen species-like smoking, aging and reduced glutathione levels-must be assessed as confounders. However, these chemicals generally have multiple effects, which also may complicate reliance on intermediate end points. To choose target populations, dosages and durations for interventions, it is essential to distinguish between overcoming a relative deficiency of the micronutrient in the diet and the circulation and providing a pharmacological dose. Selenium and beta-carotene are important examples of agents that may be protective at the high end of the normal diet-based distribution of serum values, but may be toxic-somehow-at much higher levels. We are becoming more aware that it is a long leap from associations observed or deduced in epidemiological studies to the design and demonstration of successful chemopreventive interventions with single agents or with combinations or mixtures. When interventions fail to support the hypotheses from observational epidemiology, it may be necessary to reconsider the hypotheses. Furthermore, effects may vary remarkably at different tumour sites. Publication Types: Review Review, tutorial PMID: 8923018 [PubMed - indexed for MEDLINE]
17: Food Chem Toxicol 1995 Jun;33(6):537-43 Bioactive organosulfur phytochemicals in Brassica oleracea vegetables--a review. Stoewsand GS. Department of Food Science and Technology, New York State Agricultural Experiment Station, Cornell University, Geneva 14456, USA. Sulfur-containing phytochemicals of two different kinds are present in all Brassica oleracea (Cruciferae) vegetables (cabbage, broccoli, etc.). They are glucosinolates (previously called thioglucosides) and S-methyl cysteine sulfoxide. These compounds, which are derived in plant tissue by amino acid biosynthesis, show quite different toxicological effects and appear to possess anticarcinogenic properties. Glucosinolates have been extensively studied since the mid-nineteenth century. They are present in plant foods besides Brassica vegetables with especially high levels in a number of seed meals fed to livestock. About 100 different kinds of glucosinolates are known to exist in the plant kingdom, but only about 10 are present in Brassica. The first toxic effects of isothiocyanates and other hydrolytic products from glucosinolates that were identified were goitre and a general inhibition of iodine uptake by the thyroid. Numerous studies have indicated that the hydrolytic products of at least three glucosinolates, 4-methyl-sulfinylbutyl (glucoraphanin), 2-phenylethyl (gluconasturtiin) and 3-indolylmethyl (glucobrassicin), have anticarcinogenic activity. Indole-3-carbinol, a metabolite of glucobrassicin, has shown inhibitory effects in studies of human breast and ovarian cancers. Kale poisoning, or a severe haemolytic anaemia, was discovered in cattle in Europe in the 1930s, but its link with the hydrolytic product of S-methyl cysteine sulfoxide was only shown about 35 years later. S-methyl cysteine sulfoxide and its metabolite methyl methane thiosulfinate were shown to inhibit chemically-induced genotoxicity in mice. Thus, the cancer chemopreventive effects of Brassica vegetables that have been shown in human and animal studies may be due to the presence of both types of sulfur-containing phytochemicals (i.e. certain glucosinolates and S-methyl cysteine sulfoxide). Publication Types: Review Review, tutorial PMID: 7797181 [PubMed - indexed for MEDLINE]
18: Carcinogenesis 1995 May;16(5):1101-6 Effects of dietary phenethyl isothiocyanate, ellagic acid, sulindac and calcium on the induction and progression of N-nitrosomethylbenzylamine-induced esophageal carcinogenesis in rats. Siglin JC, Barch DH, Stoner GD. Department of Pathology, Medical College of Ohio, Toledo 43699-0008, USA. The potential inhibitory effects of phenethyl isothiocyanate (PEITC), ellagic acid (EA), sulindac and supplemental dietary calcium (SDC) on N-nitrosomethylbenzylamine (NMBA)-induced esophageal carcinogenesis were evaluated in rats utilizing an abbreviated (5 week) NMBA treatment protocol which allowed administration of the putative inhibitors throughout the experiment (i.e. beginning 2 weeks prior to NMBA treatment) or following completion of NMBA dosing only. PEITC at 500 p.p.m. significantly inhibited tumor incidence and multiplicity when given before and during, but not following, NMBA treatment. Neither sulindac at 125 p.p.m. nor SDC (2% versus 0.5% in control diet) inhibited tumor development when given during or following NMBA treatment. EA, which was administered only following NMBA treatment, significantly reduced the incidence (66.7% versus 100% in NMBA controls), but not the multiplicity, of esophageal tumors at the high-dose (4000 p.p.m.) level. Together these findings indicate that: (i) PEITC selectively inhibits the induction but not the subsequent progression of NMBA-induced esophageal tumors; (ii) EA may repress esophageal tumor development when administered following NMBA treatment; (iii) at the doses administered, neither sulindac nor SDC possess significant inhibitory activity against NMBA-induced esophageal carcinogenesis in the rat. PMID: 7767971 [PubMed - indexed for MEDLINE]
19: J Cell Biochem Suppl 1995;22:195-209 Chemoprevention by isothiocyanates. Hecht SS. American Health Foundation, Naylor Dana Institute for Disease Prevention, Division of Chemical Carcinogenesis, Valhalla, NY 10595, USA. Naturally occurring and synthetic isothiocyanates are among the most effective chemopreventive agents known. A wide variety of isothiocyanates prevents cancer in the rat lung, mammary gland, esophagus, liver, small intestine, colon, and bladder. Mechanistic studies have shown that this chemopreventive activity is due to favorable modification of phase I and phase II carcinogen metabolism, resulting in increased carcinogen excretion or detoxification and decreased carcinogen DNA interactions. Most studies reported that the isothiocyanate must be present at carcinogen exposure in order to effect tumorigenesis inhibition. Our studies focus on naturally occurring isothiocyanates phenethyl isothiocyanate (PEITC) and benzyl isothiocyanate (BITC) as lung cancer inhibitors. These studies employed the major lung carcinogens in tobacco smoke, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo(a)pyrene (BaP). Combining chemopreventive agents that inhibit tumorigenesis by NNK and BaP in rodents may be effective in addicted smokers. PEITC inhibits lung tumor induction by NNK in F-344 rats and A/J mice, while BITC inhibits BaP-induced lung tumorigenesis in A/J mice; combining the two inhibits lung tumorigenesis by combined NNK and BaP in A/J mice. PEITC selectively inhibits metabolic activation of NNK in the rodent lung, while inducing glucuronidation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), one of the major NNK metabolites. Thus, PEITC decreases DNA and hemoglobin adduct formation by NNK while increasing the amounts of NNAL and its glucuronide excreted in the urine. Presently available data indicate that non-toxic doses of PEITC can inhibit the metabolic activation and carcinogenicity of NNK in rat and mouse lung; BITC has similar effects on BaP activation and tumorigenicity in mouse lung. Thus, combinations of chemopreventive agents active against different carcinogens in tobacco smoke may be useful in the chemoprevention of lung cancer. Publication Types: Review Review, tutorial PMID: 8538199 [PubMed - indexed for MEDLINE]
20: Cancer Res 1994 Apr 1;54(7 Suppl):1976s-1981s Anticarcinogenic activities of organic isothiocyanates: chemistry and mechanisms. Zhang Y, Talalay P. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205. Organic isothiocyanates block the production of tumors induced in rodents by diverse carcinogens (polycyclic aromatic hydrocarbons, azo dyes, ethionine, N-2-fluorenylacetamide, and nitrosamines). Protection is afforded by alpha-naphthyl-, beta-naphthyl-, phenyl-, benzyl-, phenethyl-, and other arylalkyl isothiocyanates against tumor development in liver, lung, mammary gland, forestomach, and esophagus. Many isothiocyanates and their glucosinolate precursors (beta-thioglucoside, N-hydroxysulfate) occur naturally and sometimes abundantly in plants consumed by humans, e.g., cruciferous vegetables. Nevertheless, the possible contributions of isothiocyanates and glucosinolates to the well recognized protective effects against cancer of high consumptions of vegetables are unclear. The anticarcinogenic effects of isothiocyanates appear to be mediated by tandem and cooperating mechanisms: (a) suppression of carcinogen activation by cytochromes P-450, probably by a combination of down-regulation of enzyme levels and direct inhibition of their catalytic activities, which thereby lower the levels of ultimate carcinogens formed; and (b) induction of Phase 2 enzymes such as glutathione transferases and NAD(P)H: quinone reductase, which detoxify any residual electrophilic metabolites generated by Phase 1 enzymes and thereby destroy their ability to damage DNA. Since isothiocyanates block carcinogenesis by dual mechanisms and are already present in substantial quantities in human diets, these agents are ideal candidates for the development of effective chemoprotection of humans against cancer. Publication Types: Review Review, tutorial PMID: 8137323 [PubMed - indexed for MEDLINE]
21: Pharmacol Toxicol 1993;72 Suppl 1:116-35 Cancer-protective factors in fruits and vegetables: biochemical and biological background. Dragsted LO, Strube M, Larsen JC. National Food Agency of Denmark, Soborg. Cancer-protective factors are present in several fruits, vegetables and commonly used spices and herbs. They can be divided into several different groups, based on their chemical structure, e.g. polyphenols, thiols, carotenoids and retinoids, carbohydrates, trace metals, terpenes, tocopherols and degradation products of glucosinolates (i.e. isothiocyanates, indoles and dithiothiols) and others. Among each of these groups of compounds are substances, which may exert their cancer-protective action by more than one biochemical mechanism. The biochemical processes of carcinogenesis are still not known in detail and probably varies with the cancer disease in question. Accordingly, the description of the biochemical backgrounds for the actions of cancer-protective factors must be based on a simplified model of the process of carcinogenesis. The model used in this presentation is a generalised initiation-promotion-conversion model, in which initiators are thought to be directly or indirectly genotoxic, promoters are visualised as substances capable of inferring a growth advantage on initiated cells and converters are believed to be genotoxic, e.g. mutagens, clastogens, recombinogens or the like. Experimental evidence for the mechanisms of action of cancer-protective agents in fruits and vegetables that protect against initiation include the scavenging effects of polyphenols on activated mutagens and carcinogens, the quenching of singlet oxygen and radicals by carotenoids, the antioxidant effects of many compounds including ascorbic acid and polyphenols, the inhibition of activating enzymes by some flavonols and tannins, the induction of oxidation- and of conjugation (protective) enzymes by indoles, isothiocyanates and dithiothiones, the shielding of sensitive structures by some polyphenols and the stimulation of DNA-repair exerted by sulphur-containing compounds. Mechanisms at the biochemical level in anti-promotion include the antioxidant effects of carotenoids and the membrane stabilizing effects reported with polyphenols, the inhibition of proteases caused by compounds from soybeans, the stimulation of immune responses seen with carotenoids and ascorbic acid and the inhibition of ornithine decarboxylase by polyphenols and carotenoids. A few inhibitors of conversion have been identified experimentally, and it can be argued on a theoretical basis, that many inhibitors of initiation should also be efficient against conversion. The mechanisms of anticarcinogenic substances in fruits and vegetables are discussed in the light of cancer prevention and inhibition. Publication Types: Review Review, tutorial PMID: 8474974 [PubMed - indexed for MEDLINE]
22: Adv Enzyme Regul 1989;28:237-50 Mechanisms of induction of enzymes that protect against chemical carcinogenesis. Talalay P. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205. A persuasive body of evidence indicates that substantial protection against chemical carcinogenesis can be achieved by induction of enzymes concerned with the metabolism of carcinogens. There are two classes of anticarcinogenic enzyme inducers: (a) monofunctional inducers (e.g., phenolic antioxidants, isothiocyanates, coumarins, thiocarbamates, cinnamates, 1,2-dithiol-3-thiones) that elevate Phase II enzymes (such as glutathione S-transferases, NAD(P)H:quinone reductase, UDP-glucuronosyl-transferases) in various tissues without significantly raising the Phase I enzyme, aryl hydrocarbon hydroxylase (cytochrome P1-450); and (b) bifunctional inducers (e.g., polycyclic aromatic hydrocarbons, flavonoids, and azo dyes) that induce both Phase I and Phase II enzymes of xenobiotic metabolism. Induction of Phase II enzymes appears to be a sufficient condition for achieving chemoprotection, and since certain Phase I enzymes are responsible for activating carcinogens to their ultimate reactive forms, selective Phase II enzyme inducers offer intrinsically safer prospects for achieving chemoprotection. Whereas induction of both Phase I and II enzymes by bifunctional inducers depends on the Ah receptor, induction of Phase II enzymes by monofunctional inducers is independent of a functional Ah receptor. Studies on the structural requirements for induction of quinone reductase [NAD(P)H:(quinone acceptor) oxidoreductase; EC 1.6.99.2] by monofunctional inducers in Hepa 1c1c7 murine hepatoma cells have revealed that such inducers contain a distinctive chemical feature (or acquire this feature by metabolism) that regulates the synthesis of this protective enzyme. The inducers are all Michael reaction acceptors characterized by olefinic (or acetylenic) linkages that are rendered electrophilic by conjugation with electron-withdrawing groups. Typical examples are alpha, beta-unsaturated aldehydes, ketones (including quinones), thioketones, sulfones, esters, nitriles and nitro groups. The potency of these inducers parallels their reactivity as Michael acceptors. These generalizations have provided mechanistic insight into the vexing question of how so many seemingly unrelated anticarcinogens induce chemoprotective enzymes. They have also led to the prediction of entirely new and unsuspected structures of inducers, with potential for chemoprotective activity. Publication Types: Review Review literature PMID: 2696344 [PubMed - indexed for MEDLINE]