Paolini Moreno, Perocco Paolo, Canistro Donatella, Valgimigli Luca, Pedulli Gian Franco, Iori Renato, Croce Clara Della, Cantelli-Forti Giorgio, Legator Marvin S, Abdel-Rahman Sherif Z
Department of Pharmacology, University of Bologna, Bologna, Italy.
Carcinogenesis. 2004 Jan;25(1):61-7. doi: 10.1093/carcin/bgg174. Epub 2003 Sep 26.
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.
食用富含水果和蔬菜的饮食似乎与降低患癌风险有关，这使得人们相信定期摄入分离出的植物化学物质可能预防癌症。近年来，十字花科蔬菜衍生的硫代葡萄糖苷代谢产物，如西兰花中的异硫氰酸酯萝卜硫素，作为潜在的癌症化学预防剂备受关注。萝卜硫素由黑芥子酶水解其硫代葡萄糖苷前体葡萄糖萝卜硫苷（GRP）释放而来，其保护作用传统上被认为与诱导II相代谢酶有关。这些II相酶参与许多致癌物和活性氧（ROS）的解毒，从而保护细胞免受DNA损伤和随后的恶性转化。虽然诱导II相酶通常被认为是有益的，但在某些情况下，这些酶也会使几种有害化学物质生物活化。此外，尽管萝卜硫素预计有好处，但它对参与多种致癌物生物活化的I相酶系统的未知影响也不应被忽视。在这里我们表明，在大鼠肺中，虽然化学预防剂萝卜硫素的生物前体GRP轻微诱导II相解毒酶，但它有力地诱导I相致癌物活化酶，包括致癌多环芳烃（PAHs）的活化剂。与这种I相诱导同时发生的是，GRP还过度产生ROS。此外，在细胞转化试验中，GRP促进了PAH苯并[a]芘向活性致癌形式的代谢活化，并且在酵母遗传毒性试验中它损害了DNA。这表明定期给予GRP实际上可能增加而不是降低患癌风险，特别是在暴露于环境诱变剂和致癌物（如烟草烟雾和某些工业环境中发现的那些）的个体中。
