Harmaline and harmalol inhibit the carcinogen-activating enzyme CYP1A1 via transcriptional and posttranslational mechanisms

Mohamed A M El Gendy, Anatoly A. Soshilov, Michael S. Denison, Ayman O S El-Kadi

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Dioxins are known to cause several human cancers through activation of the aryl hydrocarbon receptor (AhR). Harmaline and harmalol are dihydro-β-carboline compounds present in several medicinal plants such as Peganum harmala. We have previously demonstrated the ability of P. harmala extract to inhibit TCDD-mediated induction of Cyp1a1 in murine hepatoma Hepa 1c1c7 cells. Therefore, the aim of this study is to examine the effect of harmaline and its main metabolite, harmalol, on dioxin-mediated induction of CYP1A1 in human hepatoma HepG2 cells. Our results showed that harmaline and harmalol at concentrations of (0.5-12.5μM) significantly inhibited the dioxin-induced CYP1A1 at mRNA, protein and activity levels in a concentration-dependent manner. The role of AhR was determined by the inhibition of the TCDD-mediated induction of AhR-dependent luciferase activity and the AhR/ARNT/XRE formation by both harmaline and harmalol. In addition, harmaline significantly displaced [ 3H]TCDD in the competitive ligand binding assay. At posttranslational level, both harmaline and harmalol decreased the protein stability of CYP1A1, suggesting that posttranslational modifications are involved. Moreover, the posttranslational modifications of harmaline and harmalol involve ubiquitin-proteasomal pathway and direct inhibitory effects of both compounds on CYP1A1 enzyme. These data suggest that harmaline and harmalol are promising agents for preventing dioxin-mediated effects.

Original languageEnglish (US)
Pages (from-to)353-362
Number of pages10
JournalFood and Chemical Toxicology
Volume50
Issue number2
DOIs
StatePublished - Feb 2012

Fingerprint

Harmaline
Cytochrome P-450 CYP1A1
dioxins
carcinogens
Carcinogens
hydrocarbons
Peganum harmala
Aryl Hydrocarbon Receptors
receptors
Dioxins
post-translational modification
Enzymes
hepatoma
enzymes
Peganum
luciferase
Post Translational Protein Processing
ubiquitin
medicinal plants
Hepatocellular Carcinoma

Keywords

  • Aryl hydrocarbon receptor
  • Carcinogenesis
  • CYP 1A1
  • Harmaline
  • Harmalol

ASJC Scopus subject areas

  • Food Science
  • Toxicology

Cite this

Harmaline and harmalol inhibit the carcinogen-activating enzyme CYP1A1 via transcriptional and posttranslational mechanisms. / El Gendy, Mohamed A M; Soshilov, Anatoly A.; Denison, Michael S.; El-Kadi, Ayman O S.

In: Food and Chemical Toxicology, Vol. 50, No. 2, 02.2012, p. 353-362.

Research output: Contribution to journalArticle

El Gendy, Mohamed A M ; Soshilov, Anatoly A. ; Denison, Michael S. ; El-Kadi, Ayman O S. / Harmaline and harmalol inhibit the carcinogen-activating enzyme CYP1A1 via transcriptional and posttranslational mechanisms. In: Food and Chemical Toxicology. 2012 ; Vol. 50, No. 2. pp. 353-362.
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