Baldwin W S, LeBlanc G A
Department of Toxicology, North Carolina State University, Raleigh 27695.
Chem Biol Interact. 1992 Aug 14;83(2):155-69. doi: 10.1016/0009-2797(92)90043-k.
Indole-3-carbinol (I3C), a component of cruciferous vegetables, exhibits anti-carcinogenic activity in a variety of model systems. This activity has been attributed in part to the induction of cytochrome P450 CYP1A subfamily members and the resulting increased metabolic inactivation of chemical carcinogens. The present study was undertaken to assess the effects of I3C on several constitutive P450 activities that contribute to both carcinogen and steroid hormone metabolism. Mice were administered I3C in their diet at estimated daily doses of 250, 500 and 750 mg/kg for 1 week. Liver microsomes from treated and untreated mice were subsequently assayed for CYP1A-mediated ethoxy-resorufin O-deethylase (EROD) activity, estradiol 2-hydroxylase activity and seven different testosterone hydroxylase activities. I3C elevated EROD, estradiol 2-hydroxylase and testosterone 6 alpha-hydroxylase activities in a dose-dependent manner. The other six testosterone hydroxylase activities were not significantly affected by in vivo treatment with I3C. In addition to its effects on steroid hydroxylase activities, I3C also elevated NADPH-cytochrome P450 reductase activity, a necessary component to the P450 monooxygenase system. We next examined the direct in vitro effects of I3C and its acid condensation products, as are generated in the stomach following ingestion, on the P450 catalytic activities. Testosterone 6 beta-hydroxylase, the major testosterone hydroxylase activity in untreated mice, was significantly inhibited (IC50 approximately 12 micrograms/ml) by the acid condensation products of I3C. In contrast, all other P450 activities were not appreciably affected by I3C or its acid condensation products. These results indicate that I3C can elicit both inductive and suppressive effects on the constitutive P450s that participate in carcinogen and steroid hormone metabolism. This pleiotropic effect on hepatic catalytic enzymes may contribute to the anti-carcinogenic properties of this compound.
吲哚 - 3 - 甲醇（I3C）是十字花科蔬菜的一种成分，在多种模型系统中表现出抗癌活性。这种活性部分归因于细胞色素P450 CYP1A亚家族成员的诱导以及由此导致的化学致癌物代谢失活增加。本研究旨在评估I3C对几种参与致癌物和类固醇激素代谢的组成型P450活性的影响。给小鼠喂食含I3C的饲料，估计每日剂量为250、500和750 mg/kg，持续1周。随后对处理过和未处理过的小鼠的肝脏微粒体进行检测，以测定CYP1A介导的乙氧基 - 异吩嗪酮 - O - 脱乙基酶（EROD）活性、雌二醇2 - 羟化酶活性和七种不同的睾酮羟化酶活性。I3C以剂量依赖性方式提高了EROD、雌二醇2 - 羟化酶和睾酮6α - 羟化酶活性。其他六种睾酮羟化酶活性未受到I3C体内处理的显著影响。除了对类固醇羟化酶活性的影响外，I3C还提高了NADPH - 细胞色素P450还原酶活性，这是P450单加氧酶系统的一个必要组成部分。接下来，我们研究了I3C及其摄入后在胃中产生的酸缩合产物对P450催化活性的直接体外影响。未处理小鼠中主要的睾酮羟化酶活性——睾酮6β - 羟化酶，受到I3C酸缩合产物的显著抑制（IC50约为12微克/毫升）。相比之下，所有其他P450活性未受到I3C或其酸缩合产物的明显影响。这些结果表明，I3C可以对参与致癌物和类固醇激素代谢的组成型P450产生诱导和抑制作用。这种对肝脏催化酶的多效性作用可能有助于该化合物的抗癌特性。
