Jellinck P H, Forkert P G, Riddick D S, Okey A B, Michnovicz J J, Bradlow H L
Department of Biochemistry, Queen's University, Kingston, Ontario, Canada.
Biochem Pharmacol. 1993 Mar 9;45(5):1129-36. doi: 10.1016/0006-2952(93)90258-x.
The effect of route of administration on the ability of indole-3-carbinol (13C), an anticarcinogen present in cruciferous vegetables, to induce estradiol 2-hydroxylase (EH) in female rat liver microsomes was investigated and compared to that of its main gastric conversion product, 3,3'-diindolylmethane (DIM). This dimer was more potent than 13C after either oral or intraperitoneal administration and was also a better in vitro inhibitor of EH in control and 13C-induced hepatic microsomes. The induction of both CYP1A1 and 1A2 in about equal amounts by 13C and DIM as well as of CYP2B1/2 was demonstrated using monoclonal antibodies. DIM, isosafrole, beta-naphthoflavone, 3-methylcholanthrene and naringenin added in vitro inhibited EH strongly in induced microsomes but gestodene was a better inhibitor of estrogen 2-hydroxylation in liver microsomes from untreated female rats. The binding affinities of 13C and DIM to the Ah receptor were compared to that of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) by competition studies, and the IC50 values were shown to be 2.0 x 10(-9) M, 5.0 x 10(-5) M and 2.3 x 10(-3) M for TCDD, DIM and 13C, respectively. The ability of 13C or DIM to cause in vitro transformation of the Ah receptor to a form able to bind to the dioxin-responsive element-3 (DRE3) was compared to that of TCDD and shown to parallel their abilities to compete for binding of [3H]TCDD to the Ah receptor. These experiments confirm and extend the proposals that dietary indoles induce specific cytochrome P450s in rat liver by a mechanism possibly involving the Ah receptor. The induced monooxygenases, in turn, increase the synthesis of 2-hydroxylated estrogens in the competing pathways of 2- and 16 alpha-hydroxylation which decreases the levels of 16 alpha-hydroxyestrone able to form stable covalent adducts with proteins including the estrogen receptor. Such steroid-protein interaction has been correlated with mammary carcinogenesis.
研究了给药途径对十字花科蔬菜中存在的抗癌物质吲哚 - 3 - 甲醇（13C）诱导雌性大鼠肝微粒体中雌二醇2 - 羟化酶（EH）能力的影响，并将其与主要的胃转化产物3,3'-二吲哚基甲烷（DIM）进行比较。无论是口服还是腹腔注射后，这种二聚体都比13C更有效，并且在对照和13C诱导的肝微粒体中，它也是一种更好的EH体外抑制剂。使用单克隆抗体证明了13C和DIM对CYP1A1和1A2的诱导量大致相等，以及对CYP2B1/2的诱导。体外添加的DIM、异黄樟素、β - 萘黄酮、3 - 甲基胆蒽和柚皮苷在诱导的微粒体中强烈抑制EH，但孕二烯酮是未处理雌性大鼠肝微粒体中雌激素2 - 羟化作用的更好抑制剂。通过竞争研究比较了13C和DIM与Ah受体的结合亲和力与2,3,7,8 - 四氯二苯并 - p - 二恶英（TCDD）的结合亲和力，结果显示TCDD、DIM和13C的IC50值分别为2.0×10(-9) M、5.0×10(-5) M和2.3×10(-3) M。将13C或DIM在体外使Ah受体转化为能够与二恶英反应元件 - 3（DRE3）结合的形式的能力与TCDD进行比较，结果表明其与它们竞争[3H]TCDD与Ah受体结合的能力平行。这些实验证实并扩展了以下观点：膳食吲哚通过可能涉及Ah受体的机制在大鼠肝脏中诱导特定的细胞色素P450。反过来，诱导的单加氧酶在2 - 羟化和16α - 羟化的竞争途径中增加2 - 羟化雌激素的合成，这降低了能够与包括雌激素受体在内的蛋白质形成稳定共价加合物的16α - 羟基雌酮的水平。这种类固醇 - 蛋白质相互作用与乳腺癌发生相关。
