Broccoli bioactives: impact on enzyme induction, estrogen metabolism and human cancer cell growth

Estrogen-associated cancers are a leading cause of mortality and morbidity in U.S. men and women. Consumption of cruciferous vegetables, such as broccoli, cauliflower and cabbage, is associated with reduced risk for these and other cancers. The chemoprotective properties of crucifers are traditionally attributed to high levels of glucosinolates and their bioactive breakdown products. A proposed mechanism of protection against estrogen-associated cancers by cruciferous vegetables is alteration of estrogen metabolism toward formation of less estrogenic metabolites. Supplementation with the glucosinolate breakdown product indole-3-carbinol (I3C) has been shown to increase formation of 2-hydroxyestrogens, estrogen metabolites with weak estrogenic activity. However, the observed reduction in risk for estrogen-associated cancers with increased consumption of cruciferous vegetables may relate to increased formation of anticarcinogenic 2-methoxyestrogens derived from further metabolism of 2-hydroxyestrogens. In this study, glucosinolate breakdown products found in broccoli enhanced formation of 2-methoxyestradiol from the parent compound 17β-estradiol in vitro and ex vivo, mainly via upregulation of the phase I detoxification enzyme cytochrome P450 (CYP) 1A. Broccoli inhibited growth of human prostate and ovarian cancer cells via induction of apoptosis, but this was not due to formation of 2-methoxyestradiol. Compared to the purified glucosinolate breakdown products I3C and sulforaphane (SF), broccoli inhibited cancer cell growth to a greater extent. Both SF and the flavonols quercetin and kaempferol have been shown individually to upregulate activity of the phase II detoxification enzyme NAD(P)H dehydrogenase, quinone 1 (NQO1). The present study demonstrated that combinations of purified SF, quercetin and kaempferol increased NQO1 activity in a synergistic manner in murine hepatoma cells. Broccoli is an active accumulator of selenium, and the concentration of this mineral in the plant tissue may be orders of magnitude greater than that in the soil. Selenium enrichment has been shown to enhance the anticarcinogenic property of broccoli. An underlying mechanism may be upregulation of CYP1A and NQO1 activities, which may result in enhanced inactivation and subsequent excretion of potentially carcinogenic compounds. In this study, selenium enrichment resulted in increased levels of the indole glucosinolate neoglucobrassicin in the plant tissue, and a concomitant increase in CYP1A and NQO1 activities in vitro. Breakdown products of neoglucobrassicin, but not selenium, appear to account for the observed increase in CYP1A activity; their effect on NQO1 activity remains to be determined. Taken together, these results show that I3C and SF, the main bioactive glucosinolate breakdown products derived from broccoli, are not solely responsible for the anticancer effects of broccoli. Rather, other bioactive compounds present in the vegetable, alone or in combination, may contribute to the chemopreventive potential of the vegetable