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Cruciferous vegetables and lung cancer
Mutation Research 635 (2007) 146–148
Commentary
www.elsevier.com/locate/reviewsmr Community address: www.elsevier.com/locate/mutres
Cruciferous vegetables and lung cancer Andrea Sapone a,*, Alessandra Affatato a, Donatella Canistro a, Laura Pozzetti a, Massimiliano Broccoli a, Jessica Barillari b, Renato Iori b, Moreno Paolini a a
Department of Pharmacology, Molecular Toxicology Unit, Alma Mater Studiorum, University of Bologna, via Irnerio 48, Bologna, Italy b Agricultural Research Council – Research Institute for Industrial Crops (CRA-ISCI), via Corticella 133, Bologna, Italy Received 5 June 2006; received in revised form 23 October 2006; accepted 1 November 2006 Available online 15 December 2006
Keywords: Cruciferous vegetables; Lung cancer; Isothiocyanates; Glutathione S-transferases; Tobacco smoke
A number of epidemiological studies have shown an inverse relationship between cruciferous vegetable consumption (assessed by food frequency questionnaires), and cancer, especially those of lung and stomach [1]. Crucifers, such as broccoli, cauliflower, Brussel sprouts, cabbage and watercress, contain a family of secondary plant metabolites known as glucosinolates, which are fairly unique to these vegetables. Upon hydrolysis, glucosinolates yield a number of breakdown products, mostly isothiocyanates, with supposed chemopreventive properties, as shown in experimental animals [1]. Susceptibility to lung cancer seems to be affected by polymorphisms for glutathione S-transferases (GSTs), a class of enzymes involved in the metabolism of carcinogens, such as those present in tobacco smoke (e.g. polycyclic aromatic hydrocarbons). When homozygous, the most common GSTM1 or GSTT1 polymorphisms, reported in approximately 20–50% of most populations [2], result in null genotype and no enzyme production. In epidemiological studies showing an inverse association between isothiocyanate intake or excretion * Corresponding author. Tel.: +39 051 2091807; fax: +39 051 248862. E-mail addresses: [email protected] (A. Sapone), [email protected] (M. Paolini). 1383-5742/$ – see front matter # 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.mrrev.2006.11.001
and lung cancer, a gene–environment interaction has been hypothesized, with a strong protective effect in people null for the GSTM1 or GSTT1 genotype [3]. Recently, Brennan et al. supported this view showing that weekly consumption of cruciferous vegetables protects against lung cancer in patients who smoke and have null alleles for one or both GSTM1 and GSTT1 genes [4]; smokers homozygous for the inactive forms of either or both genes were reported to have high isothiocyanate concentration due to their reduced elimination capability [5]. We believe, however, that the precise role of GSTs in isothiocyanate biotransformation and in cancer prevention needs to be reconsidered. Firstly, divergent results have been obtained about the contribution of each isoform to isothiocyanate metabolism. In one investigation in vitro, among GSTM1, GSTP1, GSTA1 and GSTM4 studied for their catalytic properties with respect to gluthatione conjugation of 14 different isothiocyanates, GSTM1 was the most efficient [6]. In contrast to this observation, on the basis of another study, only the GSTT1 enzyme seems to be really involved in isothiocyanate elimination from the body [7]. Other GST isoforms (GSTM1, GSTP1, GSTA1 and GSTM4) are also induced by consumption of cruciferous vegetables and they may contribute to the overall protective effect. Even if GST alpha was induced by
A. Sapone et al. / Mutation Research 635 (2007) 146–148
consumption of cruciferous vegetables, it was reported that among GSTM1-null individuals, isothiocyanates tend to be conserved as GSTA1-sequestered conjugates that slowly revert to the free form [8]. Isothiocyanates are believed to induce GST activity and therefore the excretion of mutagens and carcinogens; however, GST also catalyzes isothiocyanate conjugation with glutathione leading, under induction, to the major excretory product. Therefore, it appears evident that in the absence of GST activity, as occurs in individuals with null genotype, elimination capabilities are reduced [5] and cancer risk can either increase or decrease. People carrying GSTM1 and GSTT1 genotypes are protected by isothiocyanate accumulation (thus prolonging their beneficial effects); on the other hand, the simultaneous reduction in the metabolism of cigarette smoke related toxins – a mixture of more than 4000 compounds – will inevitably increase their accumulation and harmful outcomes. It is difficult to imagine that a specific class of phytochemicals (acting through precise, but not yet defined, protective mechanism) can counteract the toxicity of a myriad of mutagens/carcinogens (acting by different pathways). It has been hypothesized that the beneficial isothiocyanate effects stem from their ability to boost phase II metabolism-believed detoxifyingenzymes, including GSTs [4]. How can such agents protect individuals who have very low levels of circulating GST enzymes (e.g. ‘‘not inducible’’ GSTM1 and GSTT1 null alleles)? How can such agents safeguard individuals from the toxicity of certain chemicals via phase II enzyme induction if, at the same time, this induction will concomitantly increase the bioactivation of many other procarcinogens to which they are simultaneously exposed? It should be remembered that the dual activating/detoxifying nature of such enzymes implicates chemical biotransformation as a phenomenon depending on the type of substrate and not on the enzyme involved [9]. Contrary to the general hypothesis, it has been recently reported that glucoraphanin, the natural glucosinolate bioprecursor of sulforaphane, the most evoked chemopreventative isothiocyanate found mainly in broccoli and which constitutes, alone, more than 55% of dry weight of total broccoli-glucosinolates, is a potent phase I enzyme inducer and slightly affects phase II enzymes [10]. It seems therefore that new protective mechanisms of cruciferae in general and isothiocyanates in particular should be considered. The recently discovered ability of such phytochemicals to stimulate Nrf-2 gene-dependent anti-oxidant enzymes, seems to offer a promising
147
starting point [11]. It has been proposed that isothiocyanates could inhibit cancer development through multiple mechanisms, such as reduction of oxidative stress by elevating and maintaining cellular anti-oxidants or inhibition of cell proliferation (thereby retarding or eliminating clonal expansion of initiated, transformed, and/or neoplastic cells), although the apparently conflicting pro- and anti-oxidative effects of isothiocyanates remain to be elucidated [12]. Other effects, including anti-inflammatory, anti-bacterial, and induction of differentiation might contribute to the overall protective effects of these compounds. References [1] IARC, IARC Handbooks of Cancer Prevention. Cruciferous Vegetables, Isothiocyanates, and Indoles, vol. 9, IARC Press, Lyon, France, 2004. [2] S. Garte, L. Gaspari, A.K. Alexandrie, C. Ambrosone, H. Autrup, J.L. Autrup, H. Baranova, L. Bathum, S. Benhamou, P. Boffetta, C. Bouchardy, K. Breskvar, J. Brockmoller, I. Cascorbi, M.L. Clapper, C. Coutelle, A. Daly, M. Dell’Omo, V. Dolzan, C.M. Dresler, A. Fryer, A. Haugen, D.W. Hein, A. Hildesheim, A. Hirvonen, L.L. Hsieh, M. Ingelman-Sundberg, I. Kalina, D. Kang, M. Kihara, C. Kiyohara, P. Kremers, P. Lazarus, L. Le Marchand, M.C. Lechner, E.M. van Lieshout, S. London, J.J. Manni, C.M. Maugard, S. Morita, V. NazarStewart, K. Noda, Y. Oda, F.F. Parl, R. Pastorelli, I. Persson, W.H. Peters, A. Rannug, T. Rebbeck, A. Risch, L. Roelandt, M. Romkes, D. Ryberg, J. Salagovic, B. Schoket, J. Seidegard, P.G. Shields, E. Sim, D. Sinnet, R.C. Strange, I. Stucker, H. Sugimura, J. To-Figueras, P. Vineis, M.C. Yu, E. Taioli, Metabolic gene polymorphism frequencies in control populations, Cancer Epidemiol. Biomarkers Prev. 10 (2001) 1239–1248. [3] F. Bianchini, H. Vainio, Isothiocyanates in cancer prevention, Drug Metab. Rev. 36 (2004) 655–667. [4] P. Brennan, C.C. Hsu, N. Moullan, N. Szeszenia-Dabrowska, J. Lissowska, D. Zaridze, P. Rudnai, E. Fabianova, D. Mates, V. Bencko, L. Foretova, V. Janout, F. Gemignani, A. Chabrier, J. Hall, R.J. Hung, P. Boffetta, F. Canzian, Effect of cruciferous vegetables on lung cancer in patients stratified by genetic status: a Mendelian randomisation approach, Lancet 366 (2005) 1558–1560. [5] B. Zhao, A. Seow, E.J.D. Lee, W.-T. Poh, M. Teh, P. Eng, Y.-T. Wang, W.-C. Tan, M.C. Yu, H.-P. Lee, Dietary isothiocyanates, gluthatione S-transferase -M1, T1 polymorphisms and lung cancer risk among Chinese women in Singapore, Cancer Epidemiol. Biomarkers Prev. 10 (2001) 1063–1067. [6] R.H. Kolm, U.H. Danielson, Y. Zhang, P. Talalay, B. Mannervik, Isothiocyanates as substrates for human glutathione transferases: structure-activity studies, Biochem. J. 311 (1995) 453–459. [7] A. Seow, C.Y. Shi, F.L. Chung, D. Jiao, J.H. Hankin, H.P. Lee, G.A. Coetzee, M.C. Yu, Urinary total isothiocyanates (ITC) in a population-based sample of middle-aged and older Chinese in Singapore: relationship with dietary total ITC and glutathione Stransferase M1/T1/P1 genotypes, Cancer Epidemiol. Biomarkers Prev. 7 (1998) 775–781. [8] B. Ketterer, Dietary isothiocyanates as confounding factors in the molecular epidemiology of colon cancer, Cancer Epidemiol. Biomarkers Prev. 7 (1998) 645–646.
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A. Sapone et al. / Mutation Research 635 (2007) 146–148
[9] M. Paolini, M. Nestle, Pitfalls of enzyme-based molecular anticancer dietary manipulations: food for thought, Mutat. Res. Rev. 543 (2003) 181–189. [10] M. Paolini, P. Perocco, D. Canistro, L. Valgimigli, G.F. Pedulli, R. Iori, C.D. Croce, G. Cantelli-Forti, M.S. Legator, S.Z. AbdelRahman, Induction of cytochrome P450, generation of oxidative stress, in vitro cell-transforming and DNA-damaging activities by glucoraphanin, the bioprecursor of the chemopreventive agent sulforaphane found in broccoli, Carcinogenesis 25 (2004) 61–67.
[11] A. Yanaka, S. Zhang, M. Tauchi, H. Suzuki, T. Shibahara, H. Matsui, A. Nakahara, N. Tanaka, M. Yamamoto, Role of the nrf-2 gene in protection and repair of gastric mucosa against oxidative stress, Inflammopharmacology 13 (2005) 83–90. [12] Y. Zhang, J. Li, L. Tang, Cancer-preventive isothiocyanates: dichotomous modulators of oxidative stress, Free Radic. Biol. Med. 38 (2005) 70–77.
Commentary
www.elsevier.com/locate/reviewsmr Community address: www.elsevier.com/locate/mutres
Cruciferous vegetables and lung cancer Andrea Sapone a,*, Alessandra Affatato a, Donatella Canistro a, Laura Pozzetti a, Massimiliano Broccoli a, Jessica Barillari b, Renato Iori b, Moreno Paolini a a
Department of Pharmacology, Molecular Toxicology Unit, Alma Mater Studiorum, University of Bologna, via Irnerio 48, Bologna, Italy b Agricultural Research Council – Research Institute for Industrial Crops (CRA-ISCI), via Corticella 133, Bologna, Italy Received 5 June 2006; received in revised form 23 October 2006; accepted 1 November 2006 Available online 15 December 2006
Keywords: Cruciferous vegetables; Lung cancer; Isothiocyanates; Glutathione S-transferases; Tobacco smoke
A number of epidemiological studies have shown an inverse relationship between cruciferous vegetable consumption (assessed by food frequency questionnaires), and cancer, especially those of lung and stomach [1]. Crucifers, such as broccoli, cauliflower, Brussel sprouts, cabbage and watercress, contain a family of secondary plant metabolites known as glucosinolates, which are fairly unique to these vegetables. Upon hydrolysis, glucosinolates yield a number of breakdown products, mostly isothiocyanates, with supposed chemopreventive properties, as shown in experimental animals [1]. Susceptibility to lung cancer seems to be affected by polymorphisms for glutathione S-transferases (GSTs), a class of enzymes involved in the metabolism of carcinogens, such as those present in tobacco smoke (e.g. polycyclic aromatic hydrocarbons). When homozygous, the most common GSTM1 or GSTT1 polymorphisms, reported in approximately 20–50% of most populations [2], result in null genotype and no enzyme production. In epidemiological studies showing an inverse association between isothiocyanate intake or excretion * Corresponding author. Tel.: +39 051 2091807; fax: +39 051 248862. E-mail addresses: [email protected] (A. Sapone), [email protected] (M. Paolini). 1383-5742/$ – see front matter # 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.mrrev.2006.11.001
and lung cancer, a gene–environment interaction has been hypothesized, with a strong protective effect in people null for the GSTM1 or GSTT1 genotype [3]. Recently, Brennan et al. supported this view showing that weekly consumption of cruciferous vegetables protects against lung cancer in patients who smoke and have null alleles for one or both GSTM1 and GSTT1 genes [4]; smokers homozygous for the inactive forms of either or both genes were reported to have high isothiocyanate concentration due to their reduced elimination capability [5]. We believe, however, that the precise role of GSTs in isothiocyanate biotransformation and in cancer prevention needs to be reconsidered. Firstly, divergent results have been obtained about the contribution of each isoform to isothiocyanate metabolism. In one investigation in vitro, among GSTM1, GSTP1, GSTA1 and GSTM4 studied for their catalytic properties with respect to gluthatione conjugation of 14 different isothiocyanates, GSTM1 was the most efficient [6]. In contrast to this observation, on the basis of another study, only the GSTT1 enzyme seems to be really involved in isothiocyanate elimination from the body [7]. Other GST isoforms (GSTM1, GSTP1, GSTA1 and GSTM4) are also induced by consumption of cruciferous vegetables and they may contribute to the overall protective effect. Even if GST alpha was induced by
A. Sapone et al. / Mutation Research 635 (2007) 146–148
consumption of cruciferous vegetables, it was reported that among GSTM1-null individuals, isothiocyanates tend to be conserved as GSTA1-sequestered conjugates that slowly revert to the free form [8]. Isothiocyanates are believed to induce GST activity and therefore the excretion of mutagens and carcinogens; however, GST also catalyzes isothiocyanate conjugation with glutathione leading, under induction, to the major excretory product. Therefore, it appears evident that in the absence of GST activity, as occurs in individuals with null genotype, elimination capabilities are reduced [5] and cancer risk can either increase or decrease. People carrying GSTM1 and GSTT1 genotypes are protected by isothiocyanate accumulation (thus prolonging their beneficial effects); on the other hand, the simultaneous reduction in the metabolism of cigarette smoke related toxins – a mixture of more than 4000 compounds – will inevitably increase their accumulation and harmful outcomes. It is difficult to imagine that a specific class of phytochemicals (acting through precise, but not yet defined, protective mechanism) can counteract the toxicity of a myriad of mutagens/carcinogens (acting by different pathways). It has been hypothesized that the beneficial isothiocyanate effects stem from their ability to boost phase II metabolism-believed detoxifyingenzymes, including GSTs [4]. How can such agents protect individuals who have very low levels of circulating GST enzymes (e.g. ‘‘not inducible’’ GSTM1 and GSTT1 null alleles)? How can such agents safeguard individuals from the toxicity of certain chemicals via phase II enzyme induction if, at the same time, this induction will concomitantly increase the bioactivation of many other procarcinogens to which they are simultaneously exposed? It should be remembered that the dual activating/detoxifying nature of such enzymes implicates chemical biotransformation as a phenomenon depending on the type of substrate and not on the enzyme involved [9]. Contrary to the general hypothesis, it has been recently reported that glucoraphanin, the natural glucosinolate bioprecursor of sulforaphane, the most evoked chemopreventative isothiocyanate found mainly in broccoli and which constitutes, alone, more than 55% of dry weight of total broccoli-glucosinolates, is a potent phase I enzyme inducer and slightly affects phase II enzymes [10]. It seems therefore that new protective mechanisms of cruciferae in general and isothiocyanates in particular should be considered. The recently discovered ability of such phytochemicals to stimulate Nrf-2 gene-dependent anti-oxidant enzymes, seems to offer a promising
147
starting point [11]. It has been proposed that isothiocyanates could inhibit cancer development through multiple mechanisms, such as reduction of oxidative stress by elevating and maintaining cellular anti-oxidants or inhibition of cell proliferation (thereby retarding or eliminating clonal expansion of initiated, transformed, and/or neoplastic cells), although the apparently conflicting pro- and anti-oxidative effects of isothiocyanates remain to be elucidated [12]. Other effects, including anti-inflammatory, anti-bacterial, and induction of differentiation might contribute to the overall protective effects of these compounds. References [1] IARC, IARC Handbooks of Cancer Prevention. Cruciferous Vegetables, Isothiocyanates, and Indoles, vol. 9, IARC Press, Lyon, France, 2004. [2] S. Garte, L. Gaspari, A.K. Alexandrie, C. Ambrosone, H. Autrup, J.L. Autrup, H. Baranova, L. Bathum, S. Benhamou, P. Boffetta, C. Bouchardy, K. Breskvar, J. Brockmoller, I. Cascorbi, M.L. Clapper, C. Coutelle, A. Daly, M. Dell’Omo, V. Dolzan, C.M. Dresler, A. Fryer, A. Haugen, D.W. Hein, A. Hildesheim, A. Hirvonen, L.L. Hsieh, M. Ingelman-Sundberg, I. Kalina, D. Kang, M. Kihara, C. Kiyohara, P. Kremers, P. Lazarus, L. Le Marchand, M.C. Lechner, E.M. van Lieshout, S. London, J.J. Manni, C.M. Maugard, S. Morita, V. NazarStewart, K. Noda, Y. Oda, F.F. Parl, R. Pastorelli, I. Persson, W.H. Peters, A. Rannug, T. Rebbeck, A. Risch, L. Roelandt, M. Romkes, D. Ryberg, J. Salagovic, B. Schoket, J. Seidegard, P.G. Shields, E. Sim, D. Sinnet, R.C. Strange, I. Stucker, H. Sugimura, J. To-Figueras, P. Vineis, M.C. Yu, E. Taioli, Metabolic gene polymorphism frequencies in control populations, Cancer Epidemiol. Biomarkers Prev. 10 (2001) 1239–1248. [3] F. Bianchini, H. Vainio, Isothiocyanates in cancer prevention, Drug Metab. Rev. 36 (2004) 655–667. [4] P. Brennan, C.C. Hsu, N. Moullan, N. Szeszenia-Dabrowska, J. Lissowska, D. Zaridze, P. Rudnai, E. Fabianova, D. Mates, V. Bencko, L. Foretova, V. Janout, F. Gemignani, A. Chabrier, J. Hall, R.J. Hung, P. Boffetta, F. Canzian, Effect of cruciferous vegetables on lung cancer in patients stratified by genetic status: a Mendelian randomisation approach, Lancet 366 (2005) 1558–1560. [5] B. Zhao, A. Seow, E.J.D. Lee, W.-T. Poh, M. Teh, P. Eng, Y.-T. Wang, W.-C. Tan, M.C. Yu, H.-P. Lee, Dietary isothiocyanates, gluthatione S-transferase -M1, T1 polymorphisms and lung cancer risk among Chinese women in Singapore, Cancer Epidemiol. Biomarkers Prev. 10 (2001) 1063–1067. [6] R.H. Kolm, U.H. Danielson, Y. Zhang, P. Talalay, B. Mannervik, Isothiocyanates as substrates for human glutathione transferases: structure-activity studies, Biochem. J. 311 (1995) 453–459. [7] A. Seow, C.Y. Shi, F.L. Chung, D. Jiao, J.H. Hankin, H.P. Lee, G.A. Coetzee, M.C. Yu, Urinary total isothiocyanates (ITC) in a population-based sample of middle-aged and older Chinese in Singapore: relationship with dietary total ITC and glutathione Stransferase M1/T1/P1 genotypes, Cancer Epidemiol. Biomarkers Prev. 7 (1998) 775–781. [8] B. Ketterer, Dietary isothiocyanates as confounding factors in the molecular epidemiology of colon cancer, Cancer Epidemiol. Biomarkers Prev. 7 (1998) 645–646.
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A. Sapone et al. / Mutation Research 635 (2007) 146–148
[9] M. Paolini, M. Nestle, Pitfalls of enzyme-based molecular anticancer dietary manipulations: food for thought, Mutat. Res. Rev. 543 (2003) 181–189. [10] M. Paolini, P. Perocco, D. Canistro, L. Valgimigli, G.F. Pedulli, R. Iori, C.D. Croce, G. Cantelli-Forti, M.S. Legator, S.Z. AbdelRahman, Induction of cytochrome P450, generation of oxidative stress, in vitro cell-transforming and DNA-damaging activities by glucoraphanin, the bioprecursor of the chemopreventive agent sulforaphane found in broccoli, Carcinogenesis 25 (2004) 61–67.
[11] A. Yanaka, S. Zhang, M. Tauchi, H. Suzuki, T. Shibahara, H. Matsui, A. Nakahara, N. Tanaka, M. Yamamoto, Role of the nrf-2 gene in protection and repair of gastric mucosa against oxidative stress, Inflammopharmacology 13 (2005) 83–90. [12] Y. Zhang, J. Li, L. Tang, Cancer-preventive isothiocyanates: dichotomous modulators of oxidative stress, Free Radic. Biol. Med. 38 (2005) 70–77.