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Differences in the hepatic P450-dependent metabolism of estrogen and tamoxifen in response to treatment of rats with 3,3'-diindolylmethane and its parent compound indole-3-carbinol.
Cancer Detect Prev. 2004; 28(1):72-9.CD

Abstract

Indole-3-carbinol (I3C), present in cruciferous vegetables, and its major in vivo product 3,3'-diindolylmethane (DIM), have been reported to suppress estrogen-responsive cancers. This effect may be mediated through the modification of cytochrome P450 (CYP) complement and activities leading to estrogen detoxification. We examined the effects of a 4-day treatment of female Sprague-Dawley rats with DIM at 8.4 and 42 mg/kg body weight (bwt), on the hepatic CYP protein level, CYP1A1, 1A2, 2B1/2 and 3A1/2 probe activities and CYP-dependent metabolism of 17beta-estradiol (E2) and estrone (E1). At 42 mg/kg bwt, DIM effected a small increase (2.8-fold) in CYP1A1 activity, and at both dose levels it reduced CYP3A1/2 activity by approximately 40%. At the higher dose level, DIM decreased the rates of oxidation of E2 to 4-OH-E2, 4-OH-E1, 6alpha-OH-E2 and 6(alpha+beta)-OH-E1 by 39, 44, 71 and 60%, respectively, and E1 to 6(alpha+beta)-OH-E1 by 39%. These effects were considerably different from those of I3C reported by us previously. We also examined the effects of DIM and I3C on the hepatic microsomal metabolism of tamoxifen (TAM). Whereas metabolism of TAM was unaffected by DIM, formation of N-desmethyl-TAM (and its presumed derivative) was increased approximately 3-fold by I3C at 250 mg/kg bwt. Since N-desmethyl-TAM is transformed to a genotoxic metabolite, dietary exposure to I3C may enhance hepatic carcinogenicity of TAM in the rat. The differences between I3C and DIM in CYP-mediated activities and metabolism indicate that DIM is not a proximate intermediate in the mechanism of action of I3C.

Authors+Show Affiliations

Parkin DR
Veterans Affairs Medical Center, Minneapolis, MN 55417, USA.
Malejka-Giganti D
No affiliation info available

MeSH

Analysis of VarianceAnimalsAryl Hydrocarbon HydroxylasesChromatography, High Pressure LiquidCytochrome P-450 CYP3ACytochrome P-450 Enzyme SystemEstrogensFemaleIndolesMicrosomes, LiverModels, AnimalProbabilityRandom AllocationRatsRats, Sprague-DawleySensitivity and SpecificityTamoxifen

Pub Type(s)

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

Language

eng

PubMed ID

15041081

Citation

Parkin, Daniel R., and Danuta Malejka-Giganti. "Differences in the Hepatic P450-dependent Metabolism of Estrogen and Tamoxifen in Response to Treatment of Rats With 3,3'-diindolylmethane and Its Parent Compound Indole-3-carbinol." Cancer Detection and Prevention, vol. 28, no. 1, 2004, pp. 72-9.
Parkin DR, Malejka-Giganti D. Differences in the hepatic P450-dependent metabolism of estrogen and tamoxifen in response to treatment of rats with 3,3'-diindolylmethane and its parent compound indole-3-carbinol. Cancer Detect Prev. 2004;28(1):72-9.
Parkin, D. R., & Malejka-Giganti, D. (2004). Differences in the hepatic P450-dependent metabolism of estrogen and tamoxifen in response to treatment of rats with 3,3'-diindolylmethane and its parent compound indole-3-carbinol. Cancer Detection and Prevention, 28(1), 72-9.
Parkin DR, Malejka-Giganti D. Differences in the Hepatic P450-dependent Metabolism of Estrogen and Tamoxifen in Response to Treatment of Rats With 3,3'-diindolylmethane and Its Parent Compound Indole-3-carbinol. Cancer Detect Prev. 2004;28(1):72-9. PubMed PMID: 15041081.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Differences in the hepatic P450-dependent metabolism of estrogen and tamoxifen in response to treatment of rats with 3,3'-diindolylmethane and its parent compound indole-3-carbinol. AU - Parkin,Daniel R, AU - Malejka-Giganti,Danuta, PY - 2003/11/24/accepted PY - 2004/3/26/pubmed PY - 2004/7/23/medline PY - 2004/3/26/entrez SP - 72 EP - 9 JF - Cancer detection and prevention JO - Cancer Detect Prev VL - 28 IS - 1 N2 - Indole-3-carbinol (I3C), present in cruciferous vegetables, and its major in vivo product 3,3'-diindolylmethane (DIM), have been reported to suppress estrogen-responsive cancers. This effect may be mediated through the modification of cytochrome P450 (CYP) complement and activities leading to estrogen detoxification. We examined the effects of a 4-day treatment of female Sprague-Dawley rats with DIM at 8.4 and 42 mg/kg body weight (bwt), on the hepatic CYP protein level, CYP1A1, 1A2, 2B1/2 and 3A1/2 probe activities and CYP-dependent metabolism of 17beta-estradiol (E2) and estrone (E1). At 42 mg/kg bwt, DIM effected a small increase (2.8-fold) in CYP1A1 activity, and at both dose levels it reduced CYP3A1/2 activity by approximately 40%. At the higher dose level, DIM decreased the rates of oxidation of E2 to 4-OH-E2, 4-OH-E1, 6alpha-OH-E2 and 6(alpha+beta)-OH-E1 by 39, 44, 71 and 60%, respectively, and E1 to 6(alpha+beta)-OH-E1 by 39%. These effects were considerably different from those of I3C reported by us previously. We also examined the effects of DIM and I3C on the hepatic microsomal metabolism of tamoxifen (TAM). Whereas metabolism of TAM was unaffected by DIM, formation of N-desmethyl-TAM (and its presumed derivative) was increased approximately 3-fold by I3C at 250 mg/kg bwt. Since N-desmethyl-TAM is transformed to a genotoxic metabolite, dietary exposure to I3C may enhance hepatic carcinogenicity of TAM in the rat. The differences between I3C and DIM in CYP-mediated activities and metabolism indicate that DIM is not a proximate intermediate in the mechanism of action of I3C. SN - 0361-090X UR - https://www.unboundmedicine.com/medline/citation/15041081/Differences_in_the_hepatic_P450_dependent_metabolism_of_estrogen_and_tamoxifen_in_response_to_treatment_of_rats_with_33'_diindolylmethane_and_its_parent_compound_indole_3_carbinol_ DB - PRIME DP - Unbound Medicine ER -
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