Carnosol, a constituent of zyflamend, inhibits aryl hydrocarbon receptor-mediated activation of CYP1A1 and CYP1B1 transcription and mutagenesis Academic Article uri icon

Overview

MeSH Major

  • Aryl Hydrocarbon Hydroxylases
  • Cytochrome P-450 CYP1A1
  • DNA Adducts
  • Diterpenes, Abietane
  • Mutagenesis
  • Plant Extracts
  • Receptors, Aryl Hydrocarbon
  • Transcription, Genetic

abstract

  • The aryl hydrocarbon receptor (AhR), a ligand-activated member of the basic helix-loop-helix family of transcription factors, plays a significant role in polycyclic aromatic hydrocarbon (PAH)-induced carcinogenesis. In the upper aerodigestive tract of humans, tobacco smoke, a source of PAHs, activates the AhR leading to increased expression of CYP1A1 and CYP1B1, which encode proteins that convert PAHs to genotoxic metabolites. Inhibitors of Hsp90 ATPase cause a rapid decrease in levels of AhR, an Hsp90 client protein, and thereby block PAH-mediated induction of CYP1A1 and CYP1B1. The main objective of this study was to determine whether Zyflamend, a polyherbal preparation, suppressed PAH-mediated induction of CYP1A1 and CYP1B1 and inhibited DNA adduct formation and mutagenesis. We also investigated whether carnosol, one of multiple phenolic antioxidants in Zyflamend, had similar inhibitory effects. Treatment of cell lines derived from oral leukoplakia (MSK-Leuk1) and skin (HaCaT) with benzo[a]pyrene (B[a]P), a prototypic PAH, induced CYP1A1 and CYP1B1 transcription, resulting in enhanced levels of message and protein. Both Zyflamend and carnosol suppressed these effects of B[a]P. Notably, both Zyflamend and carnosol inhibited Hsp90 ATPase activity and caused a rapid reduction in AhR levels. The formation of B[a]P-induced DNA adducts and mutagenesis was also inhibited by Zyflamend and carnosol. Collectively, these results show that Zyflamend and carnosol inhibit Hsp90 ATPase leading to reduced levels of AhR, suppression of B[a]P-mediated induction of CYP1A1 and CYP1B1, and inhibition of mutagenesis. Carnosol-mediated inhibition of Hsp90 ATPase activity can help explain the chemopreventive activity of herbs such as Rosemary, which contain this phenolic antioxidant.

publication date

  • April 2012

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3324618

Digital Object Identifier (DOI)

  • 10.1158/1940-6207.CAPR-12-0002

PubMed ID

  • 22374940

Additional Document Info

start page

  • 593

end page

  • 602

volume

  • 5

number

  • 4