Broccoli sprouts as inducers of carcinogen-detoxifying enzyme systems: clinical, dietary, and policy implications.

Cancer is the second leading cause of death in the United States; it accounts for nearly one-fourth of annual deaths (1). Although the rates of some cancers have been declining, rates of others have increased. Thus, despite advances in early detection and treatment, overall death rates from cancer have remained largely unchanged since the early 1970s, suggesting the need for a stronger research focus on prevention (2). Approaches to prevention necessarily include smoking cessation and dietary changes, because each is believed to contribute to about one-third of annual cancer deaths (3). For two decades, dietary advice to prevent cancer has emphasized fruit and vegetable consumption (4), and recent recommendations, such as those listed in Table 1, give highest priority to consuming plant-based diets (5, 6). Such advice is entirely consistent with recommendations for prevention of heart disease and other diet-related chronic diseases (4). It is supported by substantial, increasing, and extensively reviewed evidence linking intake of plant foods to impressive reductions in cancer risk at several major sites (6–11). On the basis of this evidence, researchers recently have estimated that plant-based diets prevent 20% (6) to 50% (11) of all cases of cancer. Epidemiologic and animal studies have associated certain food plants with pronounced reductions in cancer risk. Among such plants are cruciferous (mustard family) vegetables of the genus Brassica: broccoli, cabbage, caulif lower, and Brussels sprouts, among others. National committees have recommended consumption of these vegetables for cancer prevention since the early 1980s (12). What characteristics of these vegetables might protect against carcinogenesis? Fahey et al. (13) directly address this important question. Brassica vegetables contain little fat, are low in energy, and are sources of vitamins, minerals, and fiber—all aspects linked to cancer protection. They also contain a large number of phytochemicals, some of which protect against carcinogenesis in various in vitro and animal testing systems (11). Table 2 summarizes the principal attributes and components of cruciferous vegetables that singly or together might protect against carcinogenesis. The research of Fahey et al. (13) aims to identify specific phytochemicals in Brassica vegetables that may confer protection and the mechanisms by which they do so. The hypothesis underlying this work is that certain phytochemicals might raise the activity of enzyme systems that detoxify carcinogens. Several enzyme systems oxidize, reduce, or hydrolyze (phase 1) and then conjugate or otherwise affect (phase 2) drugs, metabolites, carcinogens, and other toxic chemicals, thereby increasing their polarity and excretability. Phase 1 enzymes activate or deactivate carcinogens, depending on the experimental conditions. Phase 2 enzymes are more likely to detoxify. For 20 years or more, consumption of cruciferous vegetables has been known to induce enzyme detoxification in experimental systems (12). Such observations have led Paul Talalay and his colleagues (14–16) to conduct an elegant series of studies on the effects of cruciferous vegetable extracts on phase 2 enzyme induction and animal tumorigenesis. They have developed an in vitro assay to distinguish bifunctional phytochemicals that induce both phase 1 and phase 2 enzyme systems from monofunctional phytochemicals that induce only phase 2 enzymes. They then used this assay to demonstrate that Brassica vegetables are particularly rich sources of monofunctional phase 2 inducers (14) and to identify the isothiocyanate sulforaphane as the principal phase 2 inducer in broccoli extracts (15). They also have demonstrated that sulforaphane is a dose-related inhibitor of carcinogen-induced mammary tumorigenesis in rats (16). These impressive accomplishments now have been extended to identify phase 2 inducer activity in sprouts of broccoli as well as in mature plants. Most of this activity derived from the glucosinolate precursor of sulforaphane, glucoraphanin. Because no net synthesis of phase 2 inducers occurs after sprouting, their concentration decreases as the plant grows. Extracts of broccoli sprouts contain 10–100 times the phase 2 inducer activity of mature broccoli plants and are more efficient inhibitors of rat tumorigenesis. In contrast, mature broccoli also contains significant amounts of indole compounds that induce phase 1 as well as phase 2 enzymes. Thus, sprouts would appear to offer at least two anticarcinogenic advantages over mature broccoli: they contain higher concentrations of inducers, and the inducers mainly affect phase 2 enzyme systems. On this basis, Fahey et al. (13) conclude that small amounts of cruciferous vegetable sprouts may be just as protective against cancer as larger amounts of mature plants of the same variety. These studies leave no doubt that sulforaphane does indeed induce phase 2 enzymes and inhibit carcinogenesis under these conditions. At issue, however, is the clinical significance of induction of such enzyme systems by single phytochemicals. Both phase 1 and phase 2 systems are highly multifunctional and inducible by a wide variety of dietary compounds. Food plants have evolved to contain thousands of chemicals that act as protective pesticides against infection or predation (17), and humans may consume as many as 10,000 of these compounds and their metabolic products when eating vegetables. The Ames group (17) has identified 49 such compounds in cabbage, among them several that have been tested and found mutagenic or carcinogenic in animal test systems. Table 2 identifies the classes of phytochemicals in cruciferous vegetables that contain at least one compound that has proved mutagenic or carcinogenic in such tests. Thus, cruciferous and other vegetables contain some phytochemicals that are carcinogenic and others that are anticarcinogenic in test systems. This confusing situation is complicated further by the ability of both phase 1 and phase 2 enzyme systems to inactivate some carcinogens, but activate others, depending on circumstances (18). Chemicals that induce activating enzymes also will induce activation of any other compounds present that are metabolized by the same system; the same is true of substances that