Inhibitory effects of a dietary phytochemical 3,3′-diindolylmethane on the phenobarbital-induced hepatic CYP mRNA expression and CYP-catalyzed reactions in female rats

• Published in: Food and chemical toxicology Vol. 46; no. 7; pp. 2451 - 2458
• Main Authors: Parkin, Daniel R., Lu, Yongjian, Bliss, Robin L., Malejka-Giganti, Danuta
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.07.2008; New York, NY Elsevier Science
• Subjects: 17beta-estradiol; 3,3'-diindolylmethane; Analysis of Variance; animal models; Animals; Anticarcinogenic Agents - administration & dosage; Anticarcinogenic Agents - pharmacology; Aryl Hydrocarbon Hydroxylases - antagonists & inhibitors; Aryl Hydrocarbon Hydroxylases - genetics; Aryl Hydrocarbon Hydroxylases - metabolism; beta-naphthoflavone; Biological and medical sciences; CYP activities; CYP kinetics; CYP mRNA; cytochrome P-450; Cytochrome P-450 CYP1A1 - antagonists & inhibitors; Cytochrome P-450 CYP1A1 - genetics; Cytochrome P-450 CYP1A1 - metabolism; Cytochrome P-450 CYP2B1 - antagonists & inhibitors; Cytochrome P-450 CYP2B1 - genetics; Cytochrome P-450 CYP2B1 - metabolism; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - drug effects; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; Cytochrome P450 (CYP); Dietary Supplements; Dose-Response Relationship, Drug; estradiol; Estradiol - metabolism; estrogen-dependent tumorigenesis; Female; females; flavones; gene expression; in vitro studies; In Vitro Techniques; in vivo studies; indole-3-carbinol; Indoles - administration & dosage; Indoles - chemistry; Indoles - pharmacology; isomers; Kinetics; liver; Medical sciences; messenger RNA; metabolites; microsomes; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; oxidation; Oxidation-Reduction; phytochemicals; Plant poisons toxicology; Random Allocation; Rats; Rats, Sprague-Dawley; RNA, Messenger - analysis; RNA, Messenger - metabolism; Specific Pathogen-Free Organisms; Steroid Hydroxylases - antagonists & inhibitors; Steroid Hydroxylases - genetics; Steroid Hydroxylases - metabolism; Toxicology; EROD; 3,3′-Diindolylmethane; CYP kinetics; DIM; E1; CYP mRNA; E2; E3; PROD; PB; bw; Estradiol metabolism; I3C; OH; NIFOX; BROD; CYP; β-NF; Cytochrome P450 (CYP); CYP activities; MROD; Nutrition; Rat; Digestive system; Enzyme; Psychotropic; Cytochrome P450; Liver; Rodentia; Oral administration; Hypnotic; Anticonvulsant; Metabolism; Feeding; Vertebrata; Phenobarbital; 3,3'-Diindolylmethane;Cytochrome P450 (CYP);CYP kinetics;CYP mRNA;CYP activities;Estradiol metabolism; Mammalia; Messenger RNA; Diet; Animal; Plant origin; Female; Sedative; Barbiturates
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/j.fct.2008.03.029

3,3′-Diindolylmethane (DIM), derived from indole-3-carbinol (I3C), is used as a dietary supplement for its putative anticancer effects that include suppression of mammary tumor growth in female rats. The mechanism of action DIM may involve its interaction(s) with hepatic cytochromes P450 (CYPs) catalyzing oxidations of 17β-estradiol (E2). Our study showed that DIM added to hepatic microsomes of female Sprague–Dawley rats was primarily a competitive inhibitor of β-naphthoflavone (β-NF)- or I3C-induced CYP1A1 probe activity, and a potent mixed or uncompetitive inhibitor of phenobarbital (PB)-induced CYP2B1 or CYP2B2 probe activity, respectively. Microsomal metabolites of DIM were tentatively identified as two mono-hydroxy isomers of DIM, each formed preferentially by CYP1A1- or CYP2B1/2-catalyzed reaction. Evaluation of the effects of co-treatment of rats with PB and DIM by a full factorial ANOVA showed that DIM decreased the PB-induced CYP2B1 and CYP2B2 mRNA expression levels, and the rates of 2- and 4-hydroxylation of E2, and total E2 metabolite formation. The results suggest that interactions of DIM, and/or its mono-hydroxy metabolites, with CYP2B1 and CYP2B2 found to occur in hepatic microsomes upon addition of DIM or co-treatment of rats with DIM affect the rates of relevant oxidations of E2, and potentially protect against estrogen-dependent tumorigenesis.