Two-step mechanism of induction of the gene expression of a prototypic cancer-protective enzyme by diphenols

Chem Res Toxicol. 2008 Apr;21(4):805-12. doi: 10.1021/tx7002883. Epub 2008 Mar 25.


Cancer-preventive activity by exogenous molecules can be mediated by enhancing the expression of cytoprotective enzymes [e.g, glutathione- S-transferase (GST) or NAD(P)H-quinone oxidoreductase 1 (NQO1)] via antioxidant-response elements (AREs) present in the promoter regions of their genes. Previously, potency of induction of NQO1 has been linearly correlated with the ability to release an electron from different classes of inducers, including diphenols, phenylpropenoids, and flavonoids. In the present work, we focus on the induction of NQO1 by diphenols, which we consider as a model underlying the mechanisms of action of other phenolic inducers such as phenylpropenoids and flavonoids. A two-step mechanism of NQO1 activation is proposed involving (i) oxidation of diphenol inducers to their quinone derivatives and (ii) oxidation of two highly reactive thiol groups by these quinones of a protein involved in NQO1 induction. These two putative routes are supported by linear correlations between the inducer potencies and the redox properties of diphenols and of their corresponding quinones. The linear correlations demonstrate the possibility to predict the enhanced gene expression of enzymatic defenses by diphenols from quantum mechanical calculations (i) of the ability of diphenols to release electrons and (ii) of the electron affinity of their corresponding quinones.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Antineoplastic Agents
  • Cell Line
  • Cytoskeletal Proteins / metabolism
  • Gene Expression
  • Kelch-Like ECH-Associated Protein 1
  • Mice
  • NAD(P)H Dehydrogenase (Quinone)
  • NADPH Dehydrogenase / genetics*
  • NF-E2-Related Factor 2 / metabolism
  • Oxidation-Reduction
  • Phenols / toxicity*
  • Quantitative Structure-Activity Relationship
  • Reactive Oxygen Species / metabolism


  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • Cytoskeletal Proteins
  • Keap1 protein, mouse
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • Phenols
  • Reactive Oxygen Species
  • NAD(P)H Dehydrogenase (Quinone)
  • Nqo1 protein, mouse
  • NADPH Dehydrogenase