A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure.
Consumption of vegetables, especially crucifers, reduces the risk of developing cancer. Although the mechanisms of this protection are unclear, feeding of vegetables induces enzymes of xenobiotic metabolism and thereby accelerates the metabolic disposal of xenobiotics. Induction of phase II detoxication enzymes, such as quinone reductase [NAD(P)H:(quinone-acceptor) oxidoreductase, EC 1.6.99.2] and glutathione S-transferases (EC 2.5.1.18) in rodent tissues affords protection against carcinogens and other toxic electrophiles. To determine whether enzyme induction is responsible for the protective properties of vegetables in humans requires isolation of enzyme inducers from these sources. By monitoring quinone reductase induction in cultured murine hepatoma cells as the biological assay, we have isolated and identified (-)-1-isothiocyanato-(4R)-(methylsulfinyl)butane [CH3-SO-(CH2)4-NCS, sulforaphane] as a major and very potent phase II enzyme inducer in SAGA broccoli (Brassica oleracea italica). Sulforaphane is a monofunctional inducer, like other anticarcinogenic isothiocyanates, and induces phase II enzymes selectively without the induction of aryl hydrocarbon receptor-dependent cytochromes P-450 (phase I enzymes). To elucidate the structural features responsible for the high inducer potency of sulforaphane, we synthesized racemic sulforaphane and analogues differing in the oxidation state of sulfur and the number of methylene groups: CH3-SOm-(CH2)n-NCS, where m = 0, 1, or 2 and n = 3, 4, or 5, and measured their inducer potencies in murine hepatoma cells. Sulforaphane is the most potent inducer, and the presence of oxygen on sulfur enhances potency. Sulforaphane and its sulfide and sulfone analogues induced both quinone reductase and glutathione transferase activities in several mouse tissues. The induction of detoxication enzymes by sulforaphane may be a significant component of the anticarcinogenic action of broccoli.
Zhang
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Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Talalay
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Cho
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Posner
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D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001937:Brassica; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004790:Enzyme Induction / Q000187:drug effects*; D005260:Female; D005982:Glutathione Transferase / Q000096:biosynthesis*; D017879:Isothiocyanates; D008114:Liver Neoplasms, Experimental / Q000201:enzymology*; D013058:Mass Spectrometry; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis*; D009928:Organ Specificity; D010936:Plant Extracts / Q000494:pharmacology*; D013440:Sulfides / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D013454:Sulfoxides; D013861:Thiocyanates / Q000302:isolation & purification / Q000494:pharmacology*
D000970:Antineoplastic Agents; D017879:Isothiocyanates; D010936:Plant Extracts; D013440:Sulfides; D013450:Sulfones; D013454:Sulfoxides; D013861:Thiocyanates; C073538:erysolin; C073539:erucin; D016660:NAD(P)H Dehydrogenase (Quinone); D005982:Glutathione Transferase; C016766:sulforaphane