Bradlow H L, Sepkovic D W, Telang N T, Osborne M P
Strang Cancer Research Laboratory, New York, New York 10021, USA.
Ann N Y Acad Sci. 1999;889:204-13. doi: 10.1111/j.1749-6632.1999.tb08736.x.
Previous studies from this laboratory have suggested that 2-hydroxyestrone is protective against breast cancer, whereas the other principal metabolite, 16 alpha-hydroxyestrone, and the lesser metabolite quantitatively, 4-hydroxyestrone, are potent carcinogens. Attempts to directly decrease the formation of the 16-hydroxylated metabolite were either unsuccessful or required such high levels of the therapeutic agent as to be impractical. On the other hand the concentration of the protective metabolite, 2-hydroxyestrone, proved to be readily modulated by a variety of agents, both in the direction of increased protection and the opposite direction, increased risk by a variety of agents and activities. We have focussed our attention on indole-3-carbinol, a compound found in cruciferous vegetables, and its further metabolites in the body, diindolylmethane (DIM) and indolylcarbazole (ICZ), because of its relative safety and multifaceted activities. It has been shown that it induces CyP4501A1, increasing 2-hydroxylation of estrogens, leading to the protective 2-OHE1, and also decreases CyP1B1 sharply, inhibiting 4-hydroxylation of estradiol, thereby decreasing the formation of the carcinogenic 4-OHE1. In addition to these indirect effects as a result of altered estrogen metabolism, indole-3-carbinol has been shown to have direct effects on apoptosis and cyclin D, resulting in blockage of the cell cycle. In addition to its antitumor activity in animals, it has also been shown to be effective against HPV-mediated tumors in human patients. All of these responses make the study of its behavior as a therapeutic agent of considerable interest.
该实验室之前的研究表明，2-羟基雌酮对乳腺癌具有保护作用，而另一种主要代谢产物16α-羟基雌酮以及含量较少的代谢产物4-羟基雌酮（从数量上看）则是强力致癌物。试图直接减少16-羟基化代谢产物的形成要么未成功，要么需要使用高剂量的治疗药物，以至于不切实际。另一方面，事实证明，保护性代谢产物2-羟基雌酮的浓度很容易受到多种因素的调节，这些因素既能使保护作用增强，也能使风险增加，即朝着相反的方向发展。我们将注意力集中在吲哚-3-甲醇上，它是十字花科蔬菜中发现的一种化合物，以及其在体内的进一步代谢产物二吲哚甲烷（DIM）和吲哚咔唑（ICZ），因为它相对安全且具有多方面的活性。研究表明，它能诱导细胞色素P4501A1，增加雌激素的2-羟基化，生成具有保护作用的2-羟雌酮1，同时还能大幅降低细胞色素P1B1，抑制雌二醇的4-羟基化，从而减少致癌性4-羟雌酮1的形成。除了这些因雌激素代谢改变而产生的间接影响外，吲哚-3-甲醇还被证明对细胞凋亡和细胞周期蛋白D有直接影响，从而导致细胞周期阻滞。除了在动物身上具有抗肿瘤活性外，它还被证明对人类患者中由人乳头瘤病毒介导的肿瘤有效。所有这些反应使得研究其作为治疗药物的行为具有相当大的意义。
