Journal Article

2,3,7,8-Tetrachlorodibenzo-p-dioxin and Diindolylmethanes Differentially Induce Cytochrome P450 1A1, 1B1, and 19 in H295R Human Adrenocortical Carcinoma Cells

J. Thomas Sanderson, Lennert Slobbe, Gideon W. A. Lansbergen, Stephen Safe and Martin van den Berg

in Toxicological Sciences

Volume 61, issue 1, pages 40-48
Published in print May 2001 | ISSN: 1096-6080
Published online May 2001 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/61.1.40
2,3,7,8-Tetrachlorodibenzo-p-dioxin and Diindolylmethanes Differentially Induce Cytochrome P450 1A1, 1B1, and 19 in H295R Human Adrenocortical Carcinoma Cells

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Diindolylmethane (DIM) is an acid-catalyzed condensation product of indole-3-carbinol, a constituent of cruciferous vegetables, and is formed in the stomach. DIM alters estrogen metabolism and inhibits carcinogen-induced mammary tumor growth in rodents. DIM is a weak agonist for the aryl hydrocarbon (Ah) receptor and blocks the effects of estrogens via inhibitory Ah receptor-estrogen receptor cross-talk. DIM and various structural analogs were examined in H295R cells for effects on 3 cytochrome P450 (CYP) enzymes involved in estrogen synthesis and/or metabolism: CYP1A1, CYP1B1, and CYP19 (aromatase). Aromatase activity was measured by conversion of 1β-3H-androstenedione to estrone and 3H2O. H295R cells were exposed to the test chemicals dissolved in dimethyl sulfoxide for 24 h prior to analyses. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) (0–30 nM) and DIM (0–10 μM) induced ethoxyresorufin-O-deethylase (EROD) activity, as a measure of CYP1A1 and possibly 1B1 activity, with EC50 values of about 0.3 nM and 3 μM, respectively. DIM, but not TCDD, induced aromatase activity with an apparently maximal 2-fold increase at 10 μM; higher concentrations of DIM and many of its analogs were cytotoxic. TCDD (30 nM) significantly increased CYP1A1 and 1B1 mRNA levels, but had no effect on mRNA for CYP19. DIM (3 μM) significantly increased mRNA levels for all three CYPs. DIM analogs with substitutions on the 5 and 5′ position (3 μM) induced aromatase and EROD activity, together with mRNA levels of CYP1A1, 1B1, and 19; analogs that were substituted on the central carbon of the methane group showed little or no inductive activity toward the CYPs. In conclusion, DIM and several of its analogs appear to induce CYPs via multiple yet distinct pathways in H295R human adrenocortical carcinoma cells.

Keywords: CYP1B1; CYP1A1; aromatase; CYP19; TCDD; diindolylmethane

Journal Article.  6733 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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