TitleSynergestic induction of NRF-2 gene by curcumin and sulforaphane and pharmacokinetics/metabolism of 13C/Dim in rats by UPLC/MS
NameGomez, Yury Y. (author), KONG, AH-NG (chair), Minko, Tamara (internal member), Michniak, Bonzena (internal member), Rutgers University, Graduate School - New Brunswick,
DescriptionCurcumin (CUR) and Sulforaphane (SFN) have shown remarkable cancer chemopreventive effects in numerous studies and combinations of low doses of chemopreventive agents can reduce toxicity while augmenting efficacy. The first part of the thesis investigated the chemotherapeutic effects elicited by a combination of CUR and SFN on human hepatocarcinoma
cells. The combination treatment- mediated effects on phase II/antioxidant enzymatic induction and antioxidant response element (ARE) was investigated. It was proposed that the combination of CUR and SFN could synergistically enhance the induction of ARE and the nuclear E2-factor related factor 2 (Nrf2)-mediated enzymes. Low doses of CUR and SFN significantly induced the expression of Nrf2-mediated enzymes, HO-1 and UGT1A1, promoted nuclear translocation of
Nrf2– a key regulator of phase II detoxifying /antioxidant enzymes – and synergistically induced the ARE luciferase activity. Chemical inhibitors of mRNA and protein synthesis affected the combination therapy- mediated transcriptional regulation of both HO-1 and UGT1A1. Synergism of CUR and SFN was evident at low concentrations. Such synergism in ARE-luciferase activity may partly explain the significant induction in the expression of Nrf2- mediated expression of HO-1 and UGT1A1 and the nuclear translocation of Nrf2, suggesting that a combination of low doses may be a promising strategy for cancer chemoprevention. For the second part of this thesis, a liquid chromatographic method was validated for the simultaneous analysis and pharmacokinetic evaluation of Indole-3-Carbinol (I3C), Diindolylmethane (DIM), and several I3C metabolites. I3C and DIM are naturally derived phytochemicals with promising in-vitro and
in-vivo anticarcinogenic properties. Using reversed-phase ultra performance liquid
chromatography (UPLC) coupled with mass spectrophotometry (MS), a rapid, specific, and high
throughput method was developed and validated for the quantification and identification of I3C, DIM, and other I3C metabolites in plasma. Recovery, linearity, precision, accuracy, and stability analysis fulfilled the CDER guidelines criteria. The method was successfully applied to the determination of the pharmacokinetic parameters and elucidation of metabolites of I3C or DIM
after oral, intravenous, or intraperitoneal administration to Sprague- Dawley rats.
NoteIncludes bibliographical references
Noteby Yury Y. Gomez
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.