Pharmacodynamics of dietary phytochemical indoles I3C and DIM: Induction of Nrf2-mediated phase II drug metabolizing and antioxidant genes and synergism with isothiocyanates

Constance Lay Lay Saw, Melvilí Cintrón, Tien Yuan Wu, Yue Guo, Ying Huang, Woo Sik Jeong, Ah Ng Tony Kong

Research output: Contribution to journalArticlepeer-review

96 Citations (Scopus)

Abstract

The antioxidant response element (ARE) is a critical regulatory element for the expression of many phase II drug metabolizing enzymes (DME), phase III transporters and antioxidant enzymes, mediated by the transcription factor Nrf2. The aim of this study was to examine the potential activation and synergism of Nrf2-ARE-mediated transcriptional activity between four common phytochemicals present in cruciferous vegetables; the indoles: indole-3-carbinol (I3C), 3,3′-diindolylmethane (DIM); and the isothiocyanates (ITCs): phenethyl isothiocyanate (PEITC) and sulforaphane (SFN). The cytotoxicity of the compounds was determined in a human liver hepatoma cell line (HepG2-C8). The combination index was calculated to assess the synergistic effects on the induction of ARE-mediated gene expressions. Quantitative real-time polymerase chain reaction (qPCR) was employed to measure the mRNA expressions of Nrf2 and Nrf2-mediated genes. I3C and DIM showed less cytotoxicity than SFN and PEITC. Compared with I3C, DIM was found to be a stronger inducer of ARE. Synergism was observed after combined treatments of 6.25 μm I3C + 1 μm SFN, 6.25 μm I3C + 1 μm PEITC and 6.25 μm DIM + 1 μm PEITC, while an additive effect was observed for 6.25 μm DIM + 1 μm SFN. Induction of endogenous Nrf2, phase II genes (GSTm2, UGT1A1 and NQO1) and antioxidant genes (HO-1 and SOD1) was also observed. In summary, the indole I3C or DIM alone could induce or syngergistically induce in combination with the ITCs SFN or PEITC, Nrf2-ARE-mediated gene expression, which could potentially enhance cancer chemopreventive activity.

Original languageEnglish
Pages (from-to)289-300
Number of pages12
JournalBiopharmaceutics and Drug Disposition
Volume32
Issue number5
DOIs
Publication statusPublished - Jul 2011
Externally publishedYes

Keywords

  • 3,3′-diindolylmethane (DIM)
  • antioxidant response element (ARE)
  • indole-3-carbinol (I3C)
  • isothiocyanates
  • nuclear factor (erythroid-derived 2)-like 2 (NFE2L2 or Nrf2)

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Pharmacology (medical)

Fingerprint

Dive into the research topics of 'Pharmacodynamics of dietary phytochemical indoles I3C and DIM: Induction of Nrf2-mediated phase II drug metabolizing and antioxidant genes and synergism with isothiocyanates'. Together they form a unique fingerprint.

Cite this