Generic placeholder image

Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Chemical Aspects of Biological Activity of Isothiocyanates and Indoles, the Products of Glucosinolate Decomposition

Author(s): Dominik Kołodziejski, Izabela Koss-Mikołajczyk*, Ahmad Y. Abdin, Claus Jacob and Agnieszka Bartoszek

Volume 25 , Issue 15 , 2019

Page: [1717 - 1728] Pages: 12

DOI: 10.2174/1381612825666190701151644

Price: $65


There is growing evidence that cancer chemoprevention employing natural, bioactive compounds may halt or at least slow down the different stages of carcinogenesis. A particularly advantageous effect is attributed to derivatives of sulfur-organic phytochemicals, such as glucosinolates (GLs) synthesized mainly in Brassicaceae plant family. GLs are hydrolysed enzymatically to bioactive isothiocyanates (ITC) and indoles, which exhibit strong anti-inflammatory and anti-carcinogenic activity. Highly bioavailable electrophilic ITC are of particular interest, as they can react with nucleophilic groups of important biomolecules to form dithiocarbamates, thiocarbamates and thioureas. These modifications seem responsible for the chemopreventive activity, but also for genotoxicity and mutagenicity. It was documented that ITC can permanently bind to important biomolecules such as glutathione, cytoskeleton proteins, transcription factors NF-κB and Nrf2, thiol-disulfide oxidoreductases, proteasome proteins or heat shock proteins. Furthermore, ITC may also affect epigenetic regulation of gene expression, e.g. by inhibition of histone deacetylases. Some other derivatives of glucosinolates, especially indoles, are able to form covalent bonds with nucleobases in DNA, which may result in genotoxicity and mutagenicity. This article summarizes the current state of knowledge about glucosinolates and their degradation products in terms of possible interactions with reactive groups of cellular molecules.

Keywords: Glucosinolates, isothiocyanates, indoles, chemoprevention, phytochemicals, Brassicaceae.

Ferlay J, Soerjomataram I, Ervik M, et al. Cancer Incidence and Mortality Worldwide: IARC Lyon. France: International Agency for Research on Cancer 2012.
Hail N Jr, Cortes M, Drake EN, Spallholz JE. Cancer chemoprevention: A radical perspective. Free Radic Biol Med 2008; 45(2): 97-110. []. [PMID: 18454943].
Sporn MB. Approaches to prevention of epithelial cancer during the preneoplastic period. Cancer Res 1976; 36(7 PT 2): 2699-702. [PMID: 1277177].
Walczak K, Marciniak S, Rajtar G. Cancer chemoprevention - selected molecular mechanisms. Postepy Hig Med Dosw 2017; 71(0): 149-61. [PMID: 28258675].
Gopalakrishnan A, Tony Kong AN. Anticarcinogenesis by dietary phytochemicals: Cytoprotection by Nrf2 in normal cells and cytotoxicity by modulation of transcription factors NF-κ B and AP-1 in abnormal cancer cells. Food Chem Toxicol 2008; 46(4): 1257-70. []. [PMID: 17950513].
Russo GL. Ins and outs of dietary phytochemicals in cancer chemoprevention. Biochem Pharmacol 2007; 74(4): 533-44. []. [PMID: 17382300].
Lam TK, Gallicchio L, Lindsley K, et al. Cruciferous vegetable consumption and lung cancer risk: A systematic review. Cancer Epidemiol Biomarkers Prev 2009; 18(1): 184-95. []. [PMID: 19124497].
Verhoeven DT, Goldbohm RA, van Poppel G, Verhagen H, van den Brandt PA. Epidemiological studies on brassica vegetables and cancer risk. Cancer Epidemiol Biomarkers Prev 1996; 5(9): 733-48. [PMID: 8877066].
Terry P, Wolk A, Persson I, et al. Brassica vegetables and breast cancer risk. JAMA 2001; 285(23): 2975-7. []. [PMID: 11410091].
Kristal AR, Lampe JW. Brassica vegetables and prostate cancer risk: A review of the epidemiological evidence. Nutr Cancer 2002; 42(1): 1-9. []. [PMID: 12235639].
Latté KP, Appel KE, Lampen A. Health benefits and possible risks of broccoli - an overview. Food Chem Toxicol 2011; 49(12): 3287-309. []. [PMID: 21906651].
Liu B, Mao Q, Cao M, Xie L. Cruciferous vegetables intake and risk of prostate cancer: A meta-analysis. Int J Urol 2012; 19(2): 134-41. []. [PMID: 22121852].
Fahey JW, Zalcmann AT, Talalay P. The chemical diversity and distribution of glucosinolates and isothiocyanates among plants. Phytochemistry 2001; 56(1): 5-51. []. [PMID: 11198818].
Magrath R, Bano F, Morgner M, et al. Genetics of aliphatic glucosinolates. I. Side chain elongation in Brassica napus and Arabidopsis thaliana. Heredity 1994; 72: 290-9. [].
Clarke DB. Glucosinolates, structures and analysis in food. Anal Methods 2010; 2: 310-25. [].
Mithen R. Glucosinolates – biochemistry, genetics and biological activity. Plant Growth Regul 2001; 34: 91-103. [].
Jain JC. GrootWassink JWD, Reed DW, Underhill EW. Persistent co-purification of enzymes catalyzing the sequential glucosylation and sulfation steps in glucosinolate biosynthesis. J Plant Physiol 1990; 136: 356-61. [].
Jain JC. GrootWassink JWD, Kolenovsky AD, Underhill EW. Purification and properties of 3′-phosphoadenosine-5′-phosphosulphate: Desulphoglucosino late-sulphotransferase from Brassica juncea cell cultures. Phytochemistry 1990; 29: 1425-8. [].
Morant AV, Jørgensen K, Jørgensen C, et al. β-Glucosidases as detonators of plant chemical defense. Phytochemistry 2008; 69(9): 1795-813. []. [PMID: 18472115].
Zhang Z, Ober JA, Kliebenstein DJ. The gene controlling the quantitative trait locus EPITHIOSPECIFIER MODIFIER1 alters glucosinolate hydrolysis and insect resistance in Arabidopsis. Plant Cell 2006; 18(6): 1524-36. []. [PMID: 16679459].
Wittstock U, Agerbirk N, Stauber EJ, et al. Successful herbivore attack due to metabolic diversion of a plant chemical defense. Proc Natl Acad Sci USA 2004; 101(14): 4859-64. []. [PMID: 15051878].
Gumz F, Krausze J, Eisenschmidt D, et al. The crystal structure of the thiocyanate-forming protein from Thlaspi arvense, a kelch protein involved in glucosinolate breakdown. Plant Mol Biol 2015; 89(1-2): 67-81. []. [PMID: 26260516].
Clarke JD, Dashwood RH, Ho E. Multi-targeted prevention of cancer by sulforaphane. Cancer Lett 2008; 269(2): 291-304. []. [PMID: 18504070].
Ahn YH, Hwang Y, Liu H, et al. Electrophilic tuning of the chemoprotective natural product sulforaphane. Proc Natl Acad Sci USA 2010; 107(21): 9590-5. []. [PMID: 20439747].
Agerbirk N, De Vos M, Kim JH, Jander G. Indole glucosinolate breakdown and its biological effects. Phytochem Rev 2009; 8: 101-20. [].
Chen C, Kong AN. Dietary cancer-chemopreventive compounds: From signaling and gene expression to pharmacological effects. Trends Pharmacol Sci 2005; 26(6): 318-26. []. [PMID: 15925707].
Śmiechowska A, Bartoszek A, Namieśnik J. [Cancer chemopreventive agents: Glucosinolates and their decomposition products in white cabbage (Brassica oleracea var. capitata)]. Postepy Hig Med Dosw 2008; 62: 125-40. [PMID: 18388852]
Kołodziejski D, Piekarska A, Hanschen FS, et al. Relationship between conversion rate of glucosinolates to isothiocyanates/indoles and genotoxicity of individual parts of Brassica vegetables. Eur Food Res Technol 2019; 245: 383-400. [].
DeVito SC. Designing safer nitriles Designing Safer Chemicals. Washington, DC: American Chemical Society 1996; pp. 194-223. []
Llorens J, Demêmes D, Sans A. The behavioral syndrome caused by 3,3′-iminodipropionitrile and related nitriles in the rat is associated with degeneration of the vestibular sensory hair cells. Toxicol Appl Pharmacol 1993; 123(2): 199-210. []. [PMID: 8248927].
Grubb CD, Abel S. Glucosinolate metabolism and its control. Trends Plant Sci 2006; 11(2): 89-100. []. [PMID: 16406306].
Surh YJ. Cancer chemoprevention with dietary phytochemicals. Nat Rev Cancer 2003; 3(10): 768-80. []. [PMID: 14570043].
Shapiro TA, Fahey JW, Wade KL, Stephenson KK, Talalay P. Human metabolism and excretion of cancer chemoprotective glucosinolates and isothiocyanates of cruciferous vegetables. Cancer Epidemiol Biomarkers Prev 1998; 7(12): 1091-100. [PMID: 9865427].
Piekarska A, Kołodziejski D, Pilipczuk T, et al. The influence of selenium addition during germination of Brassica seeds on health-promoting potential of sprouts. Int J Food Sci Nutr 2014; 65(6): 692-702. []. [PMID: 24827602].
De Nicola GR, Bagatta M, Pagnotta E, et al. Comparison of bioactive phytochemical content and release of isothiocyanates in selected Brassica sprouts. Food Chem 2013; 141(1): 297-303. []. [PMID: 23768361].
Koss-Mikołajczyk I, Kusznierewicz B, Wiczkowski W, Płatosz N, Parchem K, Bartoszek A. The comparison of phytochemical composition and chosen biological activities of differently pigmented Brassica vegetables. J Funct Foods 2019.
Ye L, Zhang Y. Total intracellular accumulation levels of dietary isothiocyanates determine their activity in elevation of cellular glutathione and induction of Phase 2 detoxification enzymes. Carcinogenesis 2001; 22(12): 1987-92. []. [PMID: 11751429].
Zhang Y, Callaway EC. High cellular accumulation of sulphoraphane, a dietary anticarcinogen, is followed by rapid transporter-mediated export as a glutathione conjugate. Biochem J 2002; 364(Pt 1): 301-7. []. [PMID: 11988104].
Chung FL, Jiao D, Getahun SM, Yu MC. A urinary biomarker for uptake of dietary isothiocyanates in humans. Cancer Epidemiol Biomarkers Prev 1998; 7(2): 103-8. [PMID: 9488583].
Mennicke WH, Kral T, Krumbiegel G, Rittmann N. Determination of N-acetyl-S-(N-alkylthiocarbamoyl)-L-cysteine, a principal metabolite of alkyl isothiocyanates, in rat urine. J Chromatogr A 1987; 414(1): 19-24. []. [PMID: 3571383].
Grose KR, Bjeldanes LF. Oligomerization of indole-3-carbinol in aqueous acid. Chem Res Toxicol 1992; 5(2): 188-93. []. [PMID: 1643248].
Anderton MJ, Jukes R, Lamb JH, et al. Liquid chromatographic assay for the simultaneous determination of indole-3-carbinol and its acid condensation products in plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2003; 787(2): 281-91. []. [PMID: 12650751].
Staub RE, Feng C, Onisko B, Bailey GS, Firestone GL, Bjeldanes LF. Fate of indole-3-carbinol in cultured human breast tumor cells. Chem Res Toxicol 2002; 15(2): 101-9. []. [PMID: 11849035].
Glatt H. Sulfotransferases in the bioactivation of xenobiotics. Chem Biol Interact 2000; 129(1-2): 141-70. []. [PMID: 11154739].
Glatt H, Meinl W. Pharmacogenetics of soluble sulfotransferases (SULTs). Naunyn Schmiedebergs Arch Pharmacol 2004; 369(1): 55-68. []. [PMID: 14600802].
Glatt H, Baasanjav-Gerber C, Schumacher F, et al. 1-Methoxy-3-indolylmethyl glucosinolate; a potent genotoxicant in bacterial and mammalian cells: Mechanisms of bioactivation. Chem Biol Interact 2011; 192(1-2): 81-6. []. [PMID: 20846518].
Holst B, Williamson G. A critical review of the bioavailability of glucosinolates and related compounds. Nat Prod Rep 2004; 21(3): 425-47. []. [PMID: 15162227].
Jacob C, Battaglia E, Burkholz T, Peng D, Bagrel D, Montenarh M. Control of oxidative posttranslational cysteine modifications: From intricate chemistry to widespread biological and medical applications. Chem Res Toxicol 2012; 25(3): 588-604. []. [PMID: 22106817].
Bilska A, Kryczyk A, Włodek L. [The different aspects of the biological role of glutathione]. Postepy Hig Med Dosw 2007; 61: 438-53. [PMID: 17679914]
Kensler TW, Wakabayashi N. Nrf2: Friend or foe for chemoprevention? Carcinogenesis 2010; 31(1): 90-9. []. [PMID: 19793802].
Nguyen T, Sherratt PJ, Pickett CB. Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annu Rev Pharmacol Toxicol 2003; 43: 233-60. []. [PMID: 12359864].
Finley JW. The antioxidant responsive element (ARE) may explain the protective effects of cruciferous vegetables on cancer. Nutr Rev 2003; 61(7): 250-4. []. [PMID: 12918878].
Surh YJ, Na HK. NF-kappaB and Nrf2 as prime molecular targets for chemoprevention and cytoprotection with anti-inflammatory and antioxidant phytochemicals. Genes Nutr 2008; 2(4): 313-7. []. [PMID: 18850223].
Liu H, Dinkova-Kostova AT, Talalay P. Coordinate regulation of enzyme markers for inflammation and for protection against oxidants and electrophiles. Proc Natl Acad Sci USA 2008; 105(41): 15926-31. []. [PMID: 18838692].
Krajka-Kuźniak V, Paluszczak J, Baer-Dubowska W. The Nrf2-ARE signaling pathway: An update on its regulation and possible role in cancer prevention and treatment. Pharmacol Rep 2017; 69(3): 393-402. []. [PMID: 28267640].
Giacoppo S, Galuppo M, Montaut S, et al. An overview on neuroprotective effects of isothiocyanates for the treatment of neurodegenerative diseases. Fitoterapia 2015; 106: 12-21. []. [PMID: 26254971].
Mi L, Hood BL, Stewart NA, et al. Identification of potential protein targets of isothiocyanates by proteomics. Chem Res Toxicol 2011; 24(10): 1735-43. []. [PMID: 21838287].
Mi L, Xiao Z, Hood BL, et al. Covalent binding to tubulin by isothiocyanates. A mechanism of cell growth arrest and apoptosis. J Biol Chem 2008; 283(32): 22136-46. []. [PMID: 18524779].
Dalle-Donne I, Rossi R, Milzani A, Di Simplicio P, Colombo R. The actin cytoskeleton response to oxidants: From small heat shock protein phosphorylation to changes in the redox state of actin itself. Free Radic Biol Med 2001; 31(12): 1624-32. []. [PMID: 11744337].
Hashemy SI, Johansson C, Berndt C, Lillig CH, Holmgren A. Oxidation and S-nitrosylation of cysteines in human cytosolic and mitochondrial glutaredoxins: Effects on structure and activity. J Biol Chem 2007; 282(19): 14428-36. []. [PMID: 17355958].
Mi L, Gan N, Chung FL. Isothiocyanates inhibit proteasome activity and proliferation of multiple myeloma cells. Carcinogenesis 2011; 32(2): 216-23. []. [PMID: 21109604].
Maliński M, Cichocki M. Proteasome inhibitors in cancer therapy. Adv Hyg Exp Med 2013; 67: 90-106.
Vembar SS, Brodsky JL. One step at a time: Endoplasmic reticulum-associated degradation. Nat Rev Mol Cell Biol 2008; 9(12): 944-57. []. [PMID: 19002207].
Yamamoto S, Tomita Y, Hoshida Y, et al. Increased expression of valosin-containing protein (p97) is associated with lymph node metastasis and prognosis of pancreatic ductal adenocarcinoma. Ann Surg Oncol 2004; 11(2): 165-72. []. [PMID: 14761919].
Liu Q, Levy EJ, Chirico WJ. N-Ethylmaleimide inactivates a nucleotide-free Hsp70 molecular chaperone. J Biol Chem 1996; 271(47): 29937-44. []. [PMID: 8939938].
Fuentes F, Paredes-Gonzalez X, Kong AN. Dietary glucosinolates sulforaphane, phenethyl isothiocyanate, indole-3-carbinol/3,3′ diindolylmethane: Antioxidative stress/inflammation, Nrf2, epigenetics/epigenomics and in vivo cancer chemopreventive efficacy. Curr Pharmacol Rep 2015; 1(3): 179-96. []. [PMID: 26457242].
Royston KJ, Tollefsbol TO. The epigenetic impact of cruciferous vegetables on cancer prevention. Curr Pharmacol Rep 2015; 1(1): 46-51. []. [PMID: 25774338].
Kassahun K, Davis M, Hu P, Martin B, Baillie T. Biotransformation of the naturally occurring isothiocyanate sulforaphane in the rat: Identification of phase I metabolites and glutathione conjugates. Chem Res Toxicol 1997; 10(11): 1228-33. []. [PMID: 9403174].
Nakamura T, Kawai Y, Kitamoto N, Osawa T, Kato Y. Covalent modification of lysine residues by allyl isothiocyanate in physiological conditions: Plausible transformation of isothiocyanate from thiol to amine. Chem Res Toxicol 2009; 22(3): 536-42. []. [PMID: 19216492].
Hanschen FS, Brüggemann N, Brodehl A, et al. Characterization of products from the reaction of glucosinolate-derived isothiocyanates with cysteine and lysine derivatives formed in either model systems or broccoli sprouts. J Agric Food Chem 2012; 60(31): 7735-45. []. [PMID: 22794085].
Hanschen FS, Bauer A, Mewis I, et al. Thermally induced degradation of aliphatic glucosinolates: Identification of intermediary breakdown products and proposed degradation pathways. J Agric Food Chem 2012; 60(39): 9890-9. []. [PMID: 22958137].
Kumar A, Sabbioni G. New biomarkers for monitoring the levels of isothiocyanates in humans. Chem Res Toxicol 2010; 23(4): 756-65. []. [PMID: 20131755].
Brüsewitz G, Cameron BD, Chasseaud LF, et al. The metabolism of benzyl isothiocyanate and its cysteine conjugate. Biochem J 1977; 162(1): 99-107. []. [PMID: 15557].
Sabbioni G, Turesky RJ. Biomonitoring human albumin adducts: The past, the present, and the future. Chem Res Toxicol 2017; 30(1): 332-66. []. [PMID: 27989119].
Spencer ES, Dale EJ, Gommans AL, et al. Multiple binding modes of isothiocyanates that inhibit macrophage migration inhibitory factor. Eur J Med Chem 2015; 93: 501-10. []. [PMID: 25743213].
Barknowitz G, Engst W, Schmidt S, et al. Identification and quantification of protein adducts formed by metabolites of 1-methoxy-3-indolylmethyl glucosinolate in vitro and in mouse models. Chem Res Toxicol 2014; 27(2): 188-99. []. [PMID: 24422435].
Latté KP, Appel KE, Lampen A. Health benefits and possible risks of broccoli - an overview. Food Chem Toxicol 2011; 49(12): 3287-309. []. [PMID: 21906651].
Baasanjav-Gerber C, Hollnagel HM, Brauchmann J, Iori R, Glatt H. Detection of genotoxicants in Brassicales using endogenous DNA as a surrogate target and adducts determined by 32P-postlabelling as an experimental end point. Mutagenesis 2011; 26(3): 407-13. []. [PMID: 21193518].
Baasanjav-Gerber C, Monien BH, Mewis I, et al. Identification of glucosinolate congeners able to form DNA adducts and to induce mutations upon activation by myrosinase. Mol Nutr Food Res 2011; 55(5): 783-92. []. [PMID: 21213326].
Schumacher F, Engst W, Monien BH, et al. Detection of DNA adducts originating from 1-methoxy-3-indolylmethyl glucosinolate using isotope-dilution UPLC-ESI-MS/MS. Anal Chem 2012; 84(14): 6256-62. []. [PMID: 22816785].
Schumacher F, Florian S, Schnapper A, et al. A secondary metabolite of Brassicales, 1-methoxy-3-indolylmethyl glucosinolate, as well as its degradation product, 1-methoxy-3-indolylmethyl alcohol, forms DNA adducts in the mouse, but in varying tissues and cells. Arch Toxicol 2014; 88(3): 823-36. [PMID: 24154822].
Ntalli N, Caboni P. A review of isothiocyanates biofumigation activity on plant parasitic nematodes. Phytochem Rev 2017; 16: 827-34. [].
Kassie F, Parzefall W, Musk S, et al. Genotoxic effects of crude juices from Brassica vegetables and juices and extracts from phytopharmaceutical preparations and spices of cruciferous plants origin in bacterial and mammalian cells. Chem Biol Interact 1996; 102(1): 1-16. []. [PMID: 8827059].
Martínez A, Ikken Y, Cambero M, et al. Mutagenicity and cytotoxicity of fruits and vegetables evaluated by the Ames test and 3-(4,5-dimethylthiazo-2-yl)-2,5-diphenyltetrazolium bromide 1941 (MTT) assay. Food Sci Technol Int 1999; 5: 431-7.
Wiesner M, Schreiner M, Glatt H. High mutagenic activity of juice from pak choi (Brassica rapa ssp. chinensis) sprouts due to its content of 1-methoxy-3-indolylmethyl glucosinolate, and its enhancement by elicitation with methyl jasmonate. Food Chem Toxicol 2014; 67: 10-6. []. [PMID: 24530313].
Baasanjav-Gerber C, Engst W, Florian S, et al. Glucosinolates: DNA adduct formation in vivo and mutagenicity in vitro W: Senate Commission on Food Safety of the German Research FoundationRisk Assessment of Phytochemicals in Food - Novel Approaches. Weinheim: Wiley-VCH 2010; pp. 325-34.
Lynn A, Collins A, Fuller Z, Hillman K, Ratcliffe B. Cruciferous vegetables and colo-rectal cancer. Proc Nutr Soc 2006; 65(1): 135-44. []. [PMID: 16441953].
Heres-Pulido ME, Dueñas-García I, Castañeda-Partida L, et al. Genotoxicity studies of organically grown broccoli (Brassica oleracea var. italica) and its interactions with urethane, methyl methanesulfonate and 4-nitroquinoline-1-oxide genotoxicity in the wing spot test of Drosophila melanogaster. Food Chem Toxicol 2010; 48(1): 120-8. []. [PMID: 19786056].
Bradfield C, Bjeldanes L. Dietary modification of xenobiotic metabolism: Contribution of indolylic compounds present in Brassica oleracea. J Agric Food Chem 1987; 35: 896-900. [].

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy