Induction of cytochrome P450, generation of oxidative stress and in vitro cell-transforming DNA-damaging activities by glucoraphanin, the bioprecursor of the chemopreventive agent sulforaphane found in broccoli

Abstract

The reduced cancer risk that appears to be linked to a diet rich in fruits and vegetables has fueled the belief that regular intake of isolated phytochemicals could potentially prevent cancer. In recent years, the glucosinolate metabolites derived from cruciferous vegetables, such as the isothiocyanate sulforaphane in broccoli, have gained much attention as potential cancer chemopreventive agents. The protective effect of sulforaphane, which is liberated from its glucosinolate precursor glucoraphanin (GRP) by myrosinase hydrolysis, is conventionally thought to involve the induction of Phase-II metabolizing enzymes. These Phase-II enzymes are implicated in the detoxication of many carcinogens and reactive oxygen species (ROS), thereby protecting cells against DNA damage and subsequent malignant transformation. While the induction of Phase-II enzymes is usually considered beneficial, in some cases these enzymes also bioactivate several hazardous chemicals. Furthermore, despite its projected benefits, the unknown effect of sulforaphane on Phase-I enzyme systems, which are involved in the bioactivation of a variety of carcinogens, should not be overlooked. Here we show that, in rat lungs, while GRP, the bioprecursor of the chemopreventive agent sulforaphane, slightly induced Phase-II detoxifying enzymes, it powerfully induced Phase-I carcinogen-activating enzymes, including activators of carcinogenic polycyclic aromatic hydrocarbons (PAHs). Concomitant with this Phase-I induction, GRP also over-generated ROS. Additionally, in a cell-transforming assay, GRP facilitated the metabolic activation of the PAH benzo[a]pyrene to reactive carcinogenic forms and in a yeast genotoxicity test it damaged DNA. This suggests that regular administration of GRP could actually increase rather than decrease cancer risk, especially in individuals exposed to environmental mutagens and carcinogens such as those found in tobacco smoke and in certain industrial settings.