Toxicological Sciences 61, 40-48 (2001)
Copyright © 2001 by the Society of Toxicology
BIOTRANSFORMATION AND TOXICOKINETICS |
2,3,7,8-Tetrachlorodibenzo-p-dioxin and Diindolylmethanes Differentially Induce Cytochrome P450 1A1, 1B1, and 19 in H295R Human Adrenocortical Carcinoma Cells
* Research Institute for Toxicology, Utrecht University, P.O. Box 80176, 3508 TD Utrecht, The Netherlands; and
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843-4466
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 1ß-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.
Key Words: CYP1B1; CYP1A1; aromatase; CYP19; TCDD; diindolylmethane.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. T. Sanderson The Steroid Hormone Biosynthesis Pathway as a Target for Endocrine-Disrupting Chemicals Toxicol. Sci., November 1, 2006; 94(1): 3 - 21. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. Fowke, J. D. Morrow, S. Motley, R. M. Bostick, and R. M. Ness Brassica vegetable consumption reduces urinary F2-isoprostane levels independent of micronutrient intake Carcinogenesis, October 1, 2006; 27(10): 2096 - 2102. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Gong, G. L. Firestone, and L. F. Bjeldanes 3,3'-Diindolylmethane Is a Novel Topoisomerase II{alpha} Catalytic Inhibitor That Induces S-Phase Retardation and Mitotic Delay in Human Hepatoma HepG2 Cells Mol. Pharmacol., April 1, 2006; 69(4): 1320 - 1327. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. B. M. van Duursen, J. T. Sanderson, and M. van den Berg Cytochrome P450 1A1 and 1B1 in Human Blood Lymphocytes Are Not Suitable as Biomarkers of Exposure to Dioxin-like Compounds: Polymorphisms and Interindividual Variation in Expression and Inducibility Toxicol. Sci., May 1, 2005; 85(1): 703 - 712. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. T. Sanderson, J. Hordijk, M. S. Denison, M. F. Springsteel, M. H. Nantz, and M. van den Berg Induction and Inhibition of Aromatase (CYP19) Activity by Natural and Synthetic Flavonoid Compounds in H295R Human Adrenocortical Carcinoma Cells Toxicol. Sci., November 1, 2004; 82(1): 70 - 79. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Adachi, Y. Mori, S. Matsui, and T. Matsuda Comparison of Gene Expression Patterns between 2,3,7,8-Tetrachlorodibenzo-p-dioxin and a Natural Arylhydrocarbon Receptor Ligand, Indirubin Toxicol. Sci., July 1, 2004; 80(1): 161 - 169. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. H. Carter, K. Liu, W. Ralph Jr., D. Chen, M. Qi, S. Fan, F. Yuan, E. M. Rosen, and K. J. Auborn Diindolylmethane Alters Gene Expression in Human Keratinocytes In Vitro J. Nutr., November 1, 2002; 132(11): 3314 - 3324. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. L. BRADLOW and D. W. SEPKOVIC Diet and Breast Cancer Ann. N.Y. Acad. Sci., June 1, 2002; 963(1): 247 - 267. [Abstract] [Full Text] [PDF]
|
|