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Inhibitory effects of a dietary phytochemical 3,3'-diindolylmethane on the phenobarbital-induced hepatic CYP mRNA expression and CYP-catalyzed reactions in female rats.
Food Chem Toxicol. 2008 Jul; 46(7):2451-8.FC

Abstract

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 17beta-estradiol (E2). Our study showed that DIM added to hepatic microsomes of female Sprague-Dawley rats was primarily a competitive inhibitor of beta-naphthoflavone (beta-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.

Authors+Show Affiliations

Veterans Affairs Medical Center, Minneapolis, MN 55417, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

18486294

Citation

Parkin, Daniel R., et al. "Inhibitory Effects of a Dietary Phytochemical 3,3'-diindolylmethane On the Phenobarbital-induced Hepatic CYP mRNA Expression and CYP-catalyzed Reactions in Female Rats." Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association, vol. 46, no. 7, 2008, pp. 2451-8.
Parkin DR, Lu Y, Bliss RL, et al. Inhibitory effects of a dietary phytochemical 3,3'-diindolylmethane on the phenobarbital-induced hepatic CYP mRNA expression and CYP-catalyzed reactions in female rats. Food Chem Toxicol. 2008;46(7):2451-8.
Parkin, D. R., Lu, Y., Bliss, R. L., & Malejka-Giganti, D. (2008). Inhibitory effects of a dietary phytochemical 3,3'-diindolylmethane on the phenobarbital-induced hepatic CYP mRNA expression and CYP-catalyzed reactions in female rats. Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association, 46(7), 2451-8. https://doi.org/10.1016/j.fct.2008.03.029
Parkin DR, et al. Inhibitory Effects of a Dietary Phytochemical 3,3'-diindolylmethane On the Phenobarbital-induced Hepatic CYP mRNA Expression and CYP-catalyzed Reactions in Female Rats. Food Chem Toxicol. 2008;46(7):2451-8. PubMed PMID: 18486294.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibitory effects of a dietary phytochemical 3,3'-diindolylmethane on the phenobarbital-induced hepatic CYP mRNA expression and CYP-catalyzed reactions in female rats. AU - Parkin,Daniel R, AU - Lu,Yongjian, AU - Bliss,Robin L, AU - Malejka-Giganti,Danuta, Y1 - 2008/04/06/ PY - 2007/09/24/received PY - 2008/03/18/revised PY - 2008/03/31/accepted PY - 2008/5/20/pubmed PY - 2008/8/6/medline PY - 2008/5/20/entrez SP - 2451 EP - 8 JF - Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association JO - Food Chem Toxicol VL - 46 IS - 7 N2 - 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 17beta-estradiol (E2). Our study showed that DIM added to hepatic microsomes of female Sprague-Dawley rats was primarily a competitive inhibitor of beta-naphthoflavone (beta-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. SN - 0278-6915 UR - https://www.unboundmedicine.com/medline/citation/18486294/Inhibitory_effects_of_a_dietary_phytochemical_33'_diindolylmethane_on_the_phenobarbital_induced_hepatic_CYP_mRNA_expression_and_CYP_catalyzed_reactions_in_female_rats_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0278-6915(08)00170-1 DB - PRIME DP - Unbound Medicine ER -