Genetic and metabolic effects of gluconasturtiin, a glucosinolate derived from cruciferae.
It is thought that induction of detoxifying phase-II drug metabolizing enzymes or inhibition of bioactivating phase-I by phytoalexins could protect against mutagens and neoplasia. In the search for potential naturally occurring molecular chemoprevention agents, particular attention has been devoted to isothiocyanates, which are breakdown products-via myrosinase-of glucosinolates such as gluconasturtiin (GNST), a natural constituent of cruciferae. Here, we first investigated the ability of GNST to modulate metabolizing enzymes in male Swiss Albino CD1 mice injected by gavage (24 mg/kg or 48 mg/kg b.w.) with GNST either in single or repeated (daily for four consecutive days) dose. Using selected probes to various cytochrome P450 (CYP) isoforms, a marked and generalized decrease of CYP content, NADPH-(CYP)-c-reductase and various CYP-linked monooxygenases (measuring CYP1A1, CYP2B1/2, CYP3A1/2, CYP1A2 and CYP2E1), was observed in hepatic, renal and pulmonary subcellular preparations (up to approximately 66% loss, liver). Similar behavior was recorded using the regio- and stereo-selective hydroxylation of testosterone as multibiomarker (CYP2A1 and CYP2B9, up to approximately 96% loss), as well as with the phase-II marker glutathione S-transferase (up to approximately 50% loss, liver). We also performed genotoxicity investigations, using the diploid D7 strain of yeast Saccharomyces cerevisiae as a biological test system. GNST was able to significantly induce point reverse mutation in growing cells without myrosinase, thus suggesting either a direct GNST or a CYP-linked metabolite role in the genotoxic response. On the contrary, in suspension test, the addition of myrosinase significantly increased mitotic gene conversion, probably due to the formation of GNST-derived phenylethyl isothiocyanate (PEITC) breakdown product. Taken together, our data suggest that GNST exerts a dual effect: while strongly inhibiting the microsomal (bioactivating) metabolism, GNST also possesses genotoxic activity. This concomitant mutagenic activity underlines the necessity of overall toxicological characterization of this (or any other molecule) prior to mass chemopreventive use.
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Department of Pharmacology, Biochemical Toxicology Unit, University of Bologna, Via Irnerio 48, I-40126, Bologna, Italy.
Croce
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Iori
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Barillari
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Bronzetti
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Poi
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Cini
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Caltavuturo
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Perocco
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Paolini
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D000818:Animals; D019607:Brassicaceae / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D005961:Glucosinolates / Q000378:metabolism / Q000494:pharmacology*; D017879:Isothiocyanates / Q000378:metabolism; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008168:Lung / Q000187:drug effects; D008297:Male; D051379:Mice; D009153:Mutagens / Q000378:metabolism / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000187:drug effects; D015262:Xenobiotics / Q000378:metabolism
D004791:Enzyme Inhibitors; D005961:Glucosinolates; D017879:Isothiocyanates; D009153:Mutagens; D015262:Xenobiotics; C443697:gluconasturtiin; C058305:phenethyl isothiocyanate; D003577:Cytochrome P-450 Enzyme System