Review
Glucosinolates and isothiocyanates in health and disease

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Glucosinolates and isothiocyanates have both been objects of research for more than half a century. Interest in these unique phytochemicals escalated following the discovery that sulforaphane, an isothiocyanate from broccoli, potently induces mammalian cytoprotective proteins through the Keap1–Nrf2–ARE pathway. In parallel with the advances in understanding the molecular regulation of this pathway and its critical role in protection against electrophiles and oxidants, there have been increased efforts toward translating this knowledge to improve human health and combat disease. This review focuses on the animal studies demonstrating the beneficial effects of glucosinolates and isothiocyanates in models of carcinogenesis, and cardiovascular and neurological diseases, as well as on the intervention studies of their safety, pharmacokinetics, and efficacy in humans.

Section snippets

Glucosinolates and isothiocyanates

In 1831 Robiquet and Boutron [1] isolated sinalbin from the seeds of white mustard (Sinapis alba), thus introducing the first glucosinolate to the scientific community. Since then, more than 120 distinct glucosinolate (S-β-thioglucoside N-hydroxysulfate) structures (Figure 1a) have been described, with most isolated from cruciferous (Brassicaceae) plants (Box 1) [2]. In plants, glucosinolates are accompanied by, yet physically separated from, β-thioglucosidase enzymes known as myrosinases (EC

Protection against carcinogenesis: models and mechanisms

The first evidence that isothiocyanates are beneficial for human health came from investigations in the 1960s and 1970s using rodent models of chemical carcinogenesis. In a seminal publication, Wattenberg [20] concluded that ‘dietary constituents of this nature may diminish the impact of exposures to chemical carcinogenesis’. A contemporaneous epidemiological study [21] reported that the risk for cancer of the colon and the rectum is increased among individuals with low consumption of cabbage,

Cardiovascular protection

In the spontaneously hypertensive stroke-prone rat, feeding either dried broccoli sprouts or sulforaphane decreased oxidative stress in cardiovascular and kidney tissues, as demonstrated by lower protein nitrosation and increased glutathione, glutathione reductase, and glutathione peroxidase levels 47, 52. In addition, the endothelial-dependent relaxation of the aorta was improved, the number of infiltrating activated macrophages was reduced, and the blood pressure decreased. In an

Protection of the central nervous system

Similar to carcinogenesis and cardiovascular disease, oxidative stress and chronic inflammation are central to the pathogenesis of diseases of the central nervous system, and the protective effects of isothiocyanates are evident in models of nervous tissue injury and neurodegeneration. An example is the protection against light-induced damage of the retina by sulforaphane [54]. Four days after exposure to light, mice treated with sulforaphane had higher numbers of nuclei in the photoreceptor

Protection against diabetic nephropathy and neuropathy

In a mouse model of streptozotocin-induced diabetes, sulforaphane improved renal performance and minimized pathological changes in the glomerulus [71]. Motor nerve conduction velocity, blood flow, and pain behavior were also improved [72]. These very recent findings encourage the potential development of sulforaphane as a therapeutic to alleviate metabolic disorder and protect against renal damage and pain associated with diabetes.

Restoration of skin integrity

In the epidermis, sulforaphane induces the expression of genes coding for the structural proteins keratins 16 and 17 [73]. Because keratin 17 is functionally redundant to keratin 14, the sulforaphane-dependent induction of keratin 17 was evaluated as a potential strategy for reducing skin blistering in keratin 14 knockout mice, a model for the human skin blistering disease epidermolysis bullosa simplex. Three intraperitoneal injections of sulforaphane to a pregnant mouse every other day during

Protection against Helicobacter pylori infection

Sulforaphane also protects against H. pylori infections, which are strongly associated with the development of gastric cancer [74]. Sulforaphane-rich broccoli sprouts administered to mice infected with H. pylori and maintained on a high-salt diet reduced gastric bacterial colonization, attenuated mucosal inflammation, and prevented high salt-induced gastric corpus atrophy [75]. These findings prompted a placebo-controlled intervention study in which 48 subjects infected with H. pylori were

Concluding remarks and future perspectives

There is now a wealth of evidence regarding the protective effects of isothiocyanates. Induction of cytoprotective enzymes, inhibition of inflammatory processes, and modulation of signaling pathways are among the many diverse pharmacological outcomes of exposure to isothiocyanates. Unlike most small molecule pharmacological agents that affect single targets, the intracellular targets of isothiocyanates are multiple. Activation of transcription factor Nrf2 alone, a major outcome of

Acknowledgments

We apologize to all authors whose excellent work in this field has not been cited because of space limitations. We are very grateful to our colleagues for their invaluable contributions to the studies described in this review, and especially to Paul Talalay, Jed W. Fahey, Theresa A. Shapiro, Thomas W. Kensler, and Yuesheng Zhang (all from Johns Hopkins University), and to Research Councils UK, Cancer Research UK (C20953/A10270), the American Cancer Society (RSG-07-157-01-CNE), the Royal

References (90)

  • P.K. Dash

    Sulforaphane improves cognitive function administered following traumatic brain injury

    Neurosci. Lett.

    (2009)
  • Z. Ping

    Sulforaphane protects brains against hypoxic–ischemic injury through induction of Nrf2-dependent phase 2 enzyme

    Brain Res.

    (2010)
  • L. Mao

    Transcription factor Nrf2 protects the spinal cord from inflammation produced by spinal cord injury

    J. Surg. Res.

    (2011)
  • M.A. Morse

    Effect of frequency of isothiocyanate administration on inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced pulmonary adenoma formation in A/J mice

    Cancer Lett.

    (1992)
  • Y. Kuroiwa

    Protective effects of benzyl isothiocyanate and sulforaphane but not resveratrol against initiation of pancreatic carcinogenesis in hamsters

    Cancer Lett.

    (2006)
  • J.J. Gills

    Sulforaphane prevents mouse skin tumorigenesis during the stage of promotion

    Cancer Lett.

    (2006)
  • A.T. Dinkova-Kostova

    Protection against UV-light-induced skin carcinogenesis in SKH-1 high-risk mice by sulforaphane-containing broccoli sprout extracts

    Cancer Lett.

    (2006)
  • P.J. Robiquet et al.

    Sur la semence de moutarde

    J. Pharm. Chim.

    (1831)
  • O.A. Koroleva

    Glucosinolate-accumulating S-cells in Arabidopsis leaves and flower stalks undergo programmed cell death at early stages of differentiation

    Plant J.

    (2010)
  • T.A. Shapiro

    Human metabolism and excretion of cancer chemoprotective glucosinolates and isothiocyanates of cruciferous vegetables

    Cancer Epidemiol. Biomarkers Prev.

    (1998)
  • S.M. Getahun et al.

    Conversion of glucosinolates to isothiocyanates in humans after ingestion of cooked watercress

    Cancer Epidemiol. Biomarkers Prev.

    (1999)
  • C.C. Conaway

    Disposition of glucosinolates and sulforaphane in humans after ingestion of steamed and fresh broccoli

    Nutr. Cancer

    (2000)
  • J.M. Cramer et al.

    Sulforaphane absorption and excretion following ingestion of a semi-purified broccoli powder rich in glucoraphanin and broccoli sprouts in healthy men

    Nutr. Cancer

    (2011)
  • L. Tang

    Consumption of raw cruciferous vegetables is inversely associated with bladder cancer risk

    Cancer Epidemiol. Biomarkers Prev.

    (2008)
  • Y. Zhang

    A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure

    Proc. Natl. Acad. Sci. U.S.A.

    (1992)
  • J.W. Fahey

    Broccoli sprouts: an exceptionally rich source of inducers of enzymes that protect against chemical carcinogens

    Proc. Natl. Acad. Sci. U.S.A.

    (1997)
  • P.A. Egner

    Bioavailability of sulforaphane from two broccoli sprout beverages: results of a short-term, cross-over clinical trial in Qidong, China

    Cancer Prev. Res. (Phila.)

    (2011)
  • T.A. Shapiro

    Chemoprotective glucosinolates and isothiocyanates of broccoli sprouts: metabolism and excretion in humans

    Cancer Epidemiol. Biomarkers Prev

    (2001)
  • T.A. Shapiro

    Safety, tolerance, and metabolism of broccoli sprout glucosinolates and isothiocyanates: a clinical phase I study

    Nutr. Cancer

    (2006)
  • T.W. Kensler

    Effects of glucosinolate-rich broccoli sprouts on urinary levels of aflatoxin-DNA adducts and phenanthrene tetraols in a randomized clinical trial in He Zuo township, Qidong, People's Republic of China

    Cancer Epidemiol. Biomarkers Prev.

    (2005)
  • J.W. Fahey

    Protection of humans by plant glucosinolates: efficiency of conversion of glucosinolates to isothiocyanates by the gastrointestinal microflora

    Cancer Prev. Res. (Phila)

    (2012)
  • F. Li

    Variation of glucoraphanin metabolism in vivo and ex vivo by human gut bacteria

    Br. J. Nutr.

    (2011)
  • L.W. Wattenberg

    Inhibition of carcinogenic effects of polycyclic hydrocarbons by benzyl isothiocyanate and related compounds

    J. Natl. Cancer Inst.

    (1977)
  • S. Graham

    Diet in the epidemiology of cancer of the colon and rectum

    J. Natl. Cancer Inst.

    (1978)
  • M.C. Myzak

    Sulforaphane retards the growth of human PC-3 xenografts and inhibits HDAC activity in human subjects

    Exp. Biol. Med. (Maywood)

    (2007)
  • M.J. Chen

    Apoptosis induction in primary human colorectal cancer cell lines and retarded tumor growth in SCID mice by sulforaphane

    Evid. Based Complement. Alternat. Med.

    (2012)
  • S. Kanematsu

    Sulforaphane inhibits the growth of KPL-1 human breast cancer cells in vitro and suppresses the growth and metastasis of orthotopically transplanted KPL-1 cells in female athymic mice

    Oncol. Rep.

    (2011)
  • Y. Li

    Sulforaphane potentiates the efficacy of 17-allylamino 17-demethoxygeldanamycin against pancreatic cancer through enhanced abrogation of Hsp90 chaperone function

    Nutr. Cancer

    (2011)
  • P. Talalay

    Biochemical studies on the mechanisms by which dietary antioxidants suppress mutagenic activity

    Adv. Enzyme Regul.

    (1978)
  • H.J. Prochaska

    Rapid detection of inducers of enzymes that protect against carcinogens

    Proc. Natl. Acad. Sci. U.S.A.

    (1992)
  • C.J. Harvey

    Targeting Nrf2 signaling improves bacterial clearance by alveolar macrophages in patients with COPD and in a mouse model

    Sci. Transl. Med.

    (2011)
  • S.L. Navarro

    Modulation of human serum glutathione S-transferase A1/2 concentration by cruciferous vegetables in a controlled feeding study is influenced by GSTM1 and GSTT1 genotypes

    Cancer Epidemiol. Biomarkers Prev.

    (2009)
  • A.T. Dinkova-Kostova

    Induction of the phase 2 response in mouse and human skin by sulforaphane-containing broccoli sprout extracts

    Cancer Epidemiol. Biomarkers Prev.

    (2007)
  • R.K. Thimmulappa

    Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray

    Cancer Res.

    (2002)
  • M. Traka

    Broccoli consumption interacts with GSTM1 to perturb oncogenic signalling pathways in the prostate

    PLoS ONE

    (2008)
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