Diosmin and diosmetin are agonists of the aryl hydrocarbon receptor that differentially affect cytochrome P450 1A1

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H P Ciolino1, T T Wang, G C Yeh

  • 1Cellular Defense and Carcinogenesis Section, Division of Basic Sciences, National Cancer Institute-Frederick Cancer Research and Development Center, NIH, Maryland 21702-1201, USA. hciolino@mail.ncifcrf.gov

Cancer Research
|July 14, 1998
PubMed

Insights

Diosmin and diosmetin activate the aryl hydrocarbon receptor (AhR), increasing CYP1A1 activity. However, only diosmetin inhibits carcinogen activation by blocking cytochrome P450 1A1 (CYP1A1) enzyme activity.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Cancer Research

Background:

  • The aryl hydrocarbon receptor (AhR) pathway is crucial in regulating genes involved in xenobiotic metabolism, including cytochrome P450 1A1 (CYP1A1).
  • Dysregulation of AhR signaling and CYP1A1 activity is implicated in the metabolic activation of carcinogens, contributing to cancer development.
  • Dietary compounds like diosmin and diosmetin are being investigated for their potential chemopreventive properties.

Purpose of the Study:

  • To investigate the effects of diosmin and its aglycone, diosmetin, on the AhR-mediated carcinogen activation pathway in human breast cancer cells.
  • To determine the impact of these compounds on CYP1A1 activity, gene transcription, and carcinogen metabolism.

Main Methods:

  • MCF-7 human breast epithelial cancer cells were treated with varying doses of diosmin and diosmetin.
  • Carcinogen metabolism was assessed by measuring 7,12-dimethylbenz(a)anthracene (DMBA)-DNA adducts and DMBA-induced cytotoxicity.
  • Cytochrome P450 1A1 (CYP1A1) activity was measured using ethoxyresorufin-O-deethylase assays in intact cells and isolated microsomes.
  • Gene expression analysis included measuring CYP1A1 mRNA levels and assessing AhR DNA-binding capacity.

Main Results:

  • Diosmin treatment increased DMBA metabolism and cytotoxicity, indicating enhanced carcinogen activation.
  • Diosmetin treatment decreased DMBA metabolism and cytotoxicity, suggesting inhibition of carcinogen activation.
  • Both diosmin and diosmetin acted as AhR agonists, increasing CYP1A1 transcription and activity in a dose- and time-dependent manner.
  • Diosmetin directly inhibited CYP1A1 enzyme activity, whereas diosmin did not.

Conclusions:

  • Diosmin and diosmetin are dietary agonists of the AhR, potently increasing CYP1A1 transcription and activity.
  • Diosmetin exhibits chemopreventive potential by directly inhibiting CYP1A1 activity and thus reducing carcinogen activation.
  • These findings highlight the differential effects of diosmin and diosmetin on carcinogen metabolism and suggest diosmetin as a promising agent for cancer prevention.

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