title: Pharmacodynamics of dietary phytochemical indoles I3C and DIM: Induction of Nrf2-mediated phase II drug metabolizing and antioxidant genes and synergism with isothiocyanates.
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.
authors.affiliation: Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Constance Lay-Lay
authors.initials: CL
authors.lastname: Saw
authors.forename: Melvilí
authors.initials: M
authors.lastname: Cintrón
authors.forename: Tien-Yuan
authors.initials: TY
authors.lastname: Wu
authors.forename: Yue
authors.initials: Y
authors.lastname: Guo
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.forename: Woo-Sik
authors.initials: WS
authors.lastname: Jeong
authors.forename: Ah-Ng Tony
authors.initials: AN
authors.lastname: Kong
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D017879:Isothiocyanates / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000187:drug effects / Q000235:genetics; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects / Q000235:genetics
chemical_list: D016588:Anticarcinogenic Agents; D000975:Antioxidants; D007211:Indoles; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; C016517:indole-3-carbinol; C016392:3,3'-diindolylmethane