Induction of cellular Phase 2 enzymes (e.g.,glutathione transferases, glucuronosyltransferases, NAD(P)H:quinone oxidoreductase) and elevation of glutathione levels are now recognized as effective strategies for reducing the risk of developing neoplasms caused by electrophilic carcinogens and reactive forms of oxygen. Transcriptional activation of the genes of Phase 2 enzymes is evoked by nine classes of chemical agents, many of which are present in edible plants and already widely consumed in our diets (isothiocyanates, phenols, quinones, phenylpropenoids, Michael reaction acceptors). The ultimate goals are to identify dietary Phase 2 enzyme inducers with low toxicity and consequently suitable for rapid evaluation of efficacy and long-term use in humans. This project focuses on a detailed evaluation of novel glucosinolates (the stable biological precursors of isothiocyanates) which are widely consumed and recognized as potentially valuable protectors against carcinogenesis.
Aim 1 is designed to identify edible plants that contain substantial quantities of glucosinolates with structural features that have been previously shown to result in high inducer potency; and to isolate, crystallize, and characterize these glucosinolates in adequate quantities for biological evaluation in cells and animals.
Aim 2 proposes the isolation and detailed characterization of an unusual rhamnosyloxybenzyl glucosinolate (whose corresponding isothiocyanate is an exceedingly potent Phase 2 inducer) that is abundant in all parts of the pantropical, totally edible, and widely consumed drumstick tree (Moringa oleifera). Related multiply glycosylated glucosinolates will also be isolated from various Moringa species, examined for inducer activity, and assessed for inhibition of carcinogenesis in appropriate cell and animal models.
Aim 3 will establish in healthy volunteers the absorption, pharmacokinetics, metabolism and excretion of carefully characterized plant extracts containing glucosinolates of special interest, beginning with the rhamnosyloxybenzyl glucosinolate and its cognate isothiocyanate. These pharmacokinetic studies will set the stage for the development of safe and effective dietary chemoprotectors for human use.
| Wade, Kristina L; Ito, Yoichiro; Ramarathnam, Aarthi et al. (2015) Purification of active myrosinase from plants by aqueous two-phase counter-current chromatography. Phytochem Anal 26:47-53 |
| Fahey, Jed W; Stephenson, Katherine K; Wallace, Alison J (2015) Dietary amelioration of Helicobacter infection. Nutr Res 35:461-73 |
| Kensler, Thomas W; Egner, Patricia A; Agyeman, Abena S et al. (2013) Keap1-nrf2 signaling: a target for cancer prevention by sulforaphane. Top Curr Chem 329:163-77 |
| Tsuji, Petra A; Stephenson, Katherine K; Wade, Kristina L et al. (2013) Structure-activity analysis of flavonoids: direct and indirect antioxidant, and antiinflammatory potencies and toxicities. Nutr Cancer 65:1014-25 |
| Fahey, Jed W; Stephenson, Katherine K; Wade, Kristina L et al. (2013) Urease from Helicobacter pylori is inactivated by sulforaphane and other isothiocyanates. Biochem Biophys Res Commun 435:1-7 |
| Fahey, Jed W; Wehage, Scott L; Holtzclaw, W David et al. (2012) Protection of humans by plant glucosinolates: efficiency of conversion of glucosinolates to isothiocyanates by the gastrointestinal microflora. Cancer Prev Res (Phila) 5:603-11 |
| Kensler, Thomas W; Ng, Derek; Carmella, Steven G et al. (2012) Modulation of the metabolism of airborne pollutants by glucoraphanin-rich and sulforaphane-rich broccoli sprout beverages in Qidong, China. Carcinogenesis 33:101-7 |
| Benedict, Andrea L; Knatko, Elena V; Dinkova-Kostova, Albena T (2012) The indirect antioxidant sulforaphane protects against thiopurine-mediated photooxidative stress. Carcinogenesis 33:2457-66 |
| Fahey, Jed W; Talalay, Paul; Kensler, Thomas W (2012) Notes from the field: ""green"" chemoprevention as frugal medicine. Cancer Prev Res (Phila) 5:179-88 |
| Suganuma, Hiroyuki; Fahey, Jed W; Bryan, Kelley E et al. (2011) Stimulation of phagocytosis by sulforaphane. Biochem Biophys Res Commun 405:146-51 |
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