About the Project
It has been unequivocally established through epidemiological studies conducted worldwide that intake of diets with high vegetable content afford protection against major human degenerative diseases of high mortality such as cancer and cardiovascular disease. Cruciferous vegetables such as broccoli, Brussel sprouts and watercress, are the most closely linked to reduced cancer risk. These contain substantial amounts of glucosinolates, a class of compounds unique to these vegetables that are believed to be responsible for the anticancer activity. When the vegetables are disturbed, for example during mastication, an enzyme is released that degrades glucosinolates to isothiocyanates, which are believed to mediate the biological activity of glucosinolates. Indeed, in animal models of cancer, isothiocyanates antagonised efficiently the carcinogenicity of established cancer-causing chemicals in a number of organs including lung, prostate and mammary gland, all frequent sites of human cancer. More recent work from our own laboratory has established that the intact parent glucosinolate also possesses biological activity that may contribute to the anticancer activity of cruciferous vegetables.
Glucosinolates/isothiocyanates exert their anticancer effects through a number of mechanisms, one of the principal being modulation of the metabolism of cancer-causing compounds to which we are continuously exposed in such a way as to prevent them from interacting with and damaging DNA, but instead facilitate their elimination from the body. Indeed, extensive studies emanating from our and other laboratories have shown that glucosinolates/isothiocyanates can modulate the activity of pivotal enzyme systems involved in the metabolism of cancer-causing compounds. Moreover, we recently established that isothiocyanates prevent the binding of cancer-causing chemicals to the aryl hydrocarbon receptor that plays a major, albeit poorly understood, role in the aetiology chemically-induced cancers.
The research objectives, to be achieved through in vivo and in vitro studies conducted in animal models and human volunteers, are:
• Clarify the mechanism(s) through which isothiocyanates prevent the interaction of cancer-causing chemicals with the aryl hydrocarbon receptor and its relevance to their anticancer activity.
• Define the levels of consumption of glucosinolates/isothiocyanates that afford protection against cancer-causing chemicals in human volunteers.
• All studies involving isothiocyanates have been conducted using single compounds despite the fact that we are exposed to mixtures of these. It is imperative to establish whether isothiocyanates have the potential to interact synergistically or antagonistically
• Determine the fate of glucosinolates in human volunteers following the consumption of cruciferous vegetables.
References
1. Abdull Razis AF, De Nicola G, Pagnotta E, Iori R and Ioannides C (2012) 4-Methysulfanyl-3-butenyl isothiocyanate derived from glucoraphasatin is a potent inducer of rat hepatic phase II enzymes and a potential chemopreventive agent. Arch. Toxicol., 86, 183-194.
2. Abdull Razis AF, Konsue N, Dervetzoglou M, Plant KE, Plant N and Ioannides C (2012) Phenethyl isothiocyanate, a naturally-occurring phytochemical, is an antagonist of the aryl hydrocarbon receptor. Mol. Nutr. Food Res., 56, 425-434.
3. Abdull Razis AF, Bagatta M, De Nicola GR, Iori R and Ioannides C (2011) Up-regulation of cytochrome P450 and Phase II enzyme systems in rat precision-cut rat lung slices by the intact glucosinolates, glucoraphanin and glucoerucin. Lung Cancer, 71, 298-305.
4. Hanlon N, Konsue N, Coldham N, Sauer MJ and Ioannides C (2011) Exposure to isothiocyanates suprresses urinary mutagenicity in rats treated with the heterocyclic amine IQ: Lack of association with CYP1 activity. Nut. Cancer, 63, 300-305.
5. Abdull Razis AF, Bagatta M, De Nicola GR, Iori R and Ioannides C (2011) Induction of epoxide hydrolase and glucuronosyl transferase by isothiocyanates and intact glucosinolates in precision-cut rat liver slices: importance of side-chain substituent and chirality. Arch. Toxicol., 85, 919-927.
6. Abdull Razis AF, Iori R and Ioannides C (2011) The natural chemopreventive phytochemical R-sulforaphane is a far more potent inducer of the carcinogen-detoxifying enzyme systems in rat liver and lung than the S-isomer. Intern. J. Cancer, 128, 2775-2782.
7. Konsue N, Kirkpatrick J, Kuhnert N, King LJ and Ioannides C (2010) Repeated oral administration modulates the pharmacokinetic behaviour of the chemopreventive agent phenethyl isothiocyanate in rats. Molecular Nutrition & Food Research, 54, 426-432.
8. Konsue N and Ioannides C (2010) Modulation of carcinogen-metabolising cytochromes P450 in human liver by the chemopreventive phytochemical phenethyl isothiocyanate, a constituent of cruciferous vegetables. Toxicology, 268, 184-190.
9. Konsue N and Ioannides C (2010) Phenethyl isocyanate is not the metabolite of phenethyl isothiocyanate responsible for mechanism-based inhibition of cytochrome P450. Arch. Toxicol., 84, 751-759.
10. Konsue N and Ioannides C (2010) Differential response of four human livers to modulation of phase II enzyme systems by the chemopreventive phytochemical phenethyl isothiocyanate. Molec. Nut. Food Res., 54, 1477-1485.
11. Abdull Razis AF, Bagatta M, De Nicola GR, Iori R and Ioannides C (2010) Intact glucosinolates modulate hepatic cytochrome P450 and phase II conjugation activities and may contribute directly to the chemopreventive activity of cruciferous vegetables. Toxicology, 277, 74-85.
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