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 receptordependent 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: CHSO5(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.Individuals who consume large amounts of green and yellow vegetables have a lower risk of developing cancer (1-3). Feeding of such vegetables to rodents also protects against chemical carcinogenesis (4, 5), and it results in the induction in many tissues of phase II § enzymes-e.g., quinone reductase [QR; NAD(P)H:(quinone-acceptor) oxidoreductase, EC 1.6.99.2] and glutathione S-transferases (EC 2.5.1.18) (11-17). Although much evidence suggests that induction of these enzymes is a major mechanism responsible for this protection (18)(19)(20), the precise role of enzyme induction in protection of humans requires clarification. The preceding report (21) shows that measurement of QR activity in Hepa lclc7 murine hepatoma cells provides a rapid, reliable, and convenient index of phase II enzyme inducer activity in vegetables. Using this assay (21-24), we found that cruciferous vegetables (broccoli, cauliflower, mustard, cress, brussels sprouts) were a rich source of inducer activity. We chose to investigate broccoli (Brassica oleracea italica) specifically because it is consumed in substantial quant...

Sulforaphane [1-isothiocyanato-4-(methylsulflnyl)butanej was recently isolated from one variety ofbroccoli as the major and very potent inducer of phase 2 detoxication enzymes in murine he a cells in culture. Since phase 2 enzyme inducti is often asated With reduced ptbilit of animais and their cells to the toxic and ic effects of carcinogens and other electrophiles, it was i t to ash whether sulforaphane could block c ical carngeness. In this paper we report that sulfphane and three synthetic analogues, designed as potent phase 2 enzyme inducers, block the formation of ammary tumors in Sprague4Dawley rats treated with single doses of 9,10-dimethyl-1,2-benzanthracene. The anaogues are exo-2-acety-exo-6-isothiocyanatoorbornane, endo-2-acetyl-exo-6-isothiocyanatonorbornane, and exo-2-acetyl-exo-5-isothiocyanatonorbornane. When sulforaphane and exo-2-acetyl-ero-6-isothicyanatonorbornane were administered by gavage (75 or 150 amol per day for 5 days) around the time of exposure to the carcinogen, the incidence, multipcty, and weight ofmammary tumors were g ntly reduced, and their development was delayed. The anages endo-2-acetyl-exo-6-isothocyanatonorbornane and exo-2-acetyl-exo-5-iothlocyanatonorbornane were less potent protectors. Thus, a class of functioalized isotdocyanates with an rcgenic Properties has been identified. These results validate the thesis that inducers of phase 2 enzymes in cultured cells are likely to protect against carcinogenesis.Enzymes that metabolize xenobiotics play a major role in regulating the toxic, mutagenic, and neoplastic effects ofchemical carcinogens. Much evidence indicates that the activities of phase 2 detoxication enzymes (e.g., glutathione transferases, NAD(P)H:quinone reductase, UDP-glucuronosyltransferases, and epoxide hydrolase) in particular can modulate the response of animals and their cells to carcinogen exposure. Induction of these enzymes by a wide variety of chemicals (including components of the diet) results in protection against toxicity and neoplasia (1). To identify such protective inducers and to measure their potencies, a simple cell culture system has been developed in our laboratory (2, 3). This system depends on detern ing the specific activities of quinone reductase in murine hepatoma cells grown in 96-well microtiter plates and exposed to a range of concentrations of the inducers. Such measurements not only have reliably predicted the ability of compounds to induce phase 2 enzymes in rodent tissues in vivo but also have identified several chemoprotectors against carcinogenesis. By use of this system, sulforaphane [(-)-1-isothiocyanato-4-(methylsulfinyl)butane, 1] was recently isolated from Saga broccoli as the major phase 2 enzyme inducer present in organic solvent extracts of this vegetable.Sulforaphane is of interest for three reasons: (i) it occurs naturally in a widely consumed vegetable; (ii) it is a very potent inducer of phase 2 enzymes; and (iii) it is a monofunctional inducer (4)-i.e., it elevates phase 2 detoxication enzymes without sig...

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