Glucoraphanin, the bioprecursor of the widely extolled chemopreventive agent sulforaphane found in broccoli, induces phase-I xenobiotic metabolizing enzymes and increases free radical generation in rat liver.
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Pedulli, Gian Franco
Legator, Marvin S.
Abdel-Rahman, Sherif Z.
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AbstractEpidemiological and animal studies linking high fruit and vegetable consumption to lower cancer risk have strengthened the belief that long-term administration of isolated naturally occurring dietary constituents could reduce the risk of cancer. In recent years, metabolites derived from phytoalexins, such as glucoraphanin found in broccoli and other cruciferous vegetables (Brassicaceae), have gained much attention as potential cancer chemopreventive agents. The protective effect of these micronutrients is assumed to be due to the inhibition of Phase-I carcinogen-bioactivating enzymes and/or induction of Phase-II detoxifying enzymes, an assumption that still remains uncertain. The protective effect of glucoraphanin is thought to be due to sulforaphane, an isothiocyanate metabolite produced from glucoraphanin by myrosinase. Here we show, in rat liver, that while glucoraphanin slightly induces Phase-II enzymes, it powerfully boosts Phase-I enzymes, including activators of polycyclic aromatic hydrocarbons (PAHs), nitrosamines and olefins. Induction of the cytochrome P450 (CYP) isoforms CYP1A1/2, CYP3A1/2 and CYP2E1 was confirmed by Western immunoblotting. CYP induction was paralleled by an increase in the corresponding mRNA levels. Concomitant with this Phase-I induction, we also found that glucoraphanin generated large amount of various reactive radical species, as determined by electron paramagnetic resonance (EPR) spectrometry coupled to a radical-probe technique. This suggests that long-term uncontrolled administration of glucoraphanin could actually pose a potential health hazard.
CitationMutat. Res. 2006, 595 (1-2):125-136
DescriptionDietary modulation of carcinogenesis-related pathwaysDietary item or component studied: hioglucosidic precursor glucoraphanin (GRP).(Brasicaceae)Pathways studied: up-regulation of the xenobiotic-detoxifying Phase-II enzymes and Down regulation of the xenobiotic- activating Phase-I enzymesStudy type (in vitro, animals, humans): Sprague-Dawley ratsMode of exposure (if in vivo) (acute, chronic, root of exposure): administration through dietImpact on pathway (including dose-response): CYP2E1 activity (P < 0.01) increased in rats treated with 240 mg/kg b.w. GRP (up to 1.8- and 2-fold, in males and females, respectively).CYP1A1-linked EROD monooxygenase (P < 0.01) induced (up to 4.6- and 3.4-fold, in males and females, respectively) at the higher dose.CYP2B1/2-supported PROD monooxygenase increasedup to ?5.5-fold following repeated administration of 120 mg/kg b.w. GRP, and the 'mixed' ECOD activity as well, which was (P < 0.01) induced up to ?1.8-fold, at the higher dose tested.Repeated administration of GRP: the CYP1A1/2 (7_ position), was the most affected one, reaching an 8.8-fold increase (P < 0.01) in males treated with 240 mg/kg b.w. GRPTestosterone 2_-(CYP3A1/2, CYP1A1) hydroxylase in female rats, with an 8.4-fold increase at the higher dose compared with a 4.4-fold (P < 0.01) increase recorded in malesThe CYP2B1/2-supported 16_- (CYP2B1) testosterone hydroxylase was significantly (P < 0.01) affected by the lower GRP dosage, with a 2.1- and 2.2-fold increase. KEYWORDS CLASSIFICATION: analogs & derivatives;Animals;Anticarcinogenic Agents;Biological Markers;Blotting,Northern;Blotting,Western;Brassica;chemistry;Chromatography,High Pressure Liquid;Cytochrome P-450 Enzyme System;drug effects;dietary modulation of carcinogenesis-related pathways;Dietary Supplements;enzymology;Electron Spin Resonance Spectroscopy;Fluorometry;Free Radicals;Glucose;Imidoesters;Italy;Liver;metabolism;Metabolic Detoxication,Phase I;Metabolic Detoxication,Phase II;Molecular Probes;pharmacology;Rats;Rats,Sprague-Dawley;Research;Thiocyanates;Xenobiotics.
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