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Development and validation of a rapid UPLC/MS method for the simultaneous determination of I3C, DIM, and related metabolites and its application to pharmacokinetics studies

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Journal of Chinese Pharmaceutical Sciences 2016年第7期25卷 477-488页

作者： yury gomez Hu Wang Ah-Ng Tony Kong Graduate Program in Pharmaceutical Science Ernest Mario School of Pharmacy Rutgers The State University of New Jersey Department of Pharmaceutics Ernest Mario School of Pharmacy Rutgers The State University of New Jersey

Indole-3-carbinol(I3C) and diindolylmethane(DIM) are naturally derived dietary phytochemicals with promising anti-cancer properties that have been demonstrated both in vitro and in vivo. Using reversed-phase ultra-performance liquid chromatography(UPLC) coupled with mass spectrometry(MS), a rapid, specific, and high throughput method was developed and validated for the quantification and identification of I3 C, DIM, and other I3 C metabolites in plasma. Samples containing I3 C or DIM and the internal standard 4-methoxy indole(IS) were extracted using a liquid-liquid extraction technique. The mean recovery was 96.21% for I3 C and 108.5% for DIM. Separation was achieved using a Waters Acquity UPLC HSS T3, 1.8 μm, 2.1 mm×150 mm column and acetonitrile–water gradient elution. The flow rate was 0.3 m L/min and the run time was 9 min. The limits of detection and quantification for I3 C and DIM were 15 ng/m L and 25 ng/m L, respectively. Calibration curves for I3 C and DIM were linear(r2>0.99) over a concentration range of 0.025–20 μg/m L. Precision, accuracy, and stability analysis fulfilled the CDER guidelines criteria. The method was successfully applied to the determination of the pharmacokinetic parameters of I3 C or DIM after oral, intravenous, or intraperitoneal administration to Sprague Dawley rats. The method described here is superior over existing analytical methods for I3 C and its metabolites in terms of sensitivity, speed, and separation.

关键词： UPLC/MS Indole-3-Carbinol Diindolylmethane Pharmacokinetics Single-dose administration Sprague-Dawley Rats

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Nrf2-mediated antioxidant and detoxifying enzyme induction by a combination of curcumin and sulforaphane

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Journal of Chinese Pharmaceutical Sciences 2016年第8期25卷 559-569页

作者： Francisco Fuentes yury gomez Ximena Paredes-Gonzalez Avantika Barve Sujit Nair Siwang Yu Constance Lay Lay Saw Ah-Ng Tony Kong Facultad de Agronomia e Ingenieria Forestal Pontificia Universidad Cato1ica de Chile Casilla 306-22 Santiago Chile Department of Pharmaceutics Ernest Mario School of Pharmacy Rutgers The State University of New Jersey New Jersey 08854 USA Novartis Institutes for Biomedical Research East Hanover NJ-07470 USA Amrita Cancer Discovery Biology Laboratory Amrita Vishwa Vidyapeetham University Amritapuri Clappana P.O. Kollam Kerala-690525 India School of Pharmaceutical Sciences Peking University Health Science Center Beo'ing 100191 China

The dietary phytochemicals curcumin （CUR） and sulforaphane （SFN） have shown remarkable cancer chemopreventive effects in many model systems. This study was designed to investigate the induction of Nrf2-mediated antioxidant enzymes by combining doses of CUR and SFN and the effect of their combination on the Nrf2-ARE （antioxidant response element） response in HepG2-C8 cells. We hypothesized that the combination of the polyphenol CUR and the isothiocyanate SFN could enhance the induction of AREs and Nrf2-target enzymes. HepG2-C8 cells were treated with a combination of low doses of CUR, SFN or both. The induction of Nrf2-mediated antioxidant and phase II detoxifying enzymes-heme oxygenase-1 （HO-I） and UDP-glucuronosyltransferase-1A （UGT1A）-was measured by real-time RT-PCR and western blotting. ARE-luciferase activity was also quantified. Low doses of CUR （10 ~tM） and SFN （12.5 ~tM） significantly induced the expression of HO-1 and UGT 1 A1 proteins. Through the use of chemical inhibitors of mRNA and protein synthesis, the combination of CUR and SFN was shown to affect the transcriptional regulation of both HO-1 and UGT1A1. Additionally, the combination of CUR and SFN synergistically induced the expression of Nrf2- and ARE-luciferase activity in HepG2-C8 cells. Thus, CUR and SFN at low concentrations augment therapeutic effects in HepG2-C8 cells. The enhanced ARE-luciferase activity of combined CUR and SFN treatment could partly explain the significant induction of the Nrf2-target enzymes HO-1 and UGT1A1. Taken together, our results suggest that combining low doses of CUR and SNF could be a promising strategy for cancer chemoprevention in humans.

关键词： Antioxidant response element, Curcumin, HepG2-C8 cell-s, HO-1, Nrf2, Sulforaphane, UGT 1A1

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