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| AH RECEPTOR-BINDING PROPERTIES OF INDOLE CARBINOLS AND INDUCTION OF HEPATIC ESTRADIOL HYDROXYLATION |
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| Author(s): JELLINCK PH, FORKERT PG, RIDDICK DS, OKEY AB, MICHNOVICZ JJ, BRADLOW HL |
| Source: BIOCHEMICAL PHARMACOLOGY Volume: 45 Issue: 5 Pages: 1129-1136 Published: MAR 9 1993 |
| Times Cited: 114 References: 51 |
| Abstract: The effect of route of administration on the ability of indole-3-carbinol (I3C), 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 I3C after either oral or intraperitoneal administration and was also a better in vitro inhibitor of EH in control and I3C-induced hepatic microsomes. The induction of both CYP1A1 and 1A2 in about equal amounts by I3C 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 I3C 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 I3C, respectively. The ability of I3C 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 [H-3]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 16alpha-hydroxylation which decreases the levels of 16alpha-hydroxyestrone able to form stable covalent adducts with proteins including the estrogen receptor. Such steroid-protein interaction has been correlated with mammary carcinogenesis. |
| Document Type: Article |
| Language: English |
| Reprint Address: JELLINCK, PH (reprint author), QUEENS UNIV, DEPT BIOCHEM, KINGSTON K7L 3N6, ONTARIO CANADA |
Addresses:
1. QUEENS UNIV, DEPT ANAT, KINGSTON K7L 3N6, ONTARIO CANADA
2. UNIV TORONTO, DEPT PHARMACOL, TORONTO M5S 1A1, ONTARIO CANADA
3. INST HORMONE RES, NEW YORK, NY USA |
| Publisher: PERGAMON-ELSEVIER SCIENCE LTD, THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD, ENGLAND OX5 1GB |
| Subject Category: Pharmacology & Pharmacy |
| IDS Number: KT666 |
| ISSN: 0006-2952 |
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