Publications (62) View all
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Article: In vitro and in vivo assessment of cytochrome P450-mediated herb-drug interaction of Ssang-hwa-tang.
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ABSTRACT: We have evaluated the herb-drug interaction potential of Ssang-hwa-tang (SHT) mediated by cytochrome P450 (CYP) inhibition/induction. Further, the effects of fermentation on the CYP-mediated herb-drug interaction potential were determined. SHT showed inhibitory activity toward CYP1A2, but not 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4 in human liver microsomes. The results of the enzyme kinetic study suggested that the SHT-induced CYP1A2 inhibition is mixed reversible inhibition. The hepatic CYP expression and activity in rats treated with SHT were examined. The expression/activity of CYP2E1 increased as a result of SHT extract treatment (P<0.005 or P<0.001, respectively), which raises the possibility that SHT may increase the toxicity of environmental toxicants through the elevation of CYP2E1-mediated metabolic activation. SHT fermentation using Lactobacillus fermentum or Lactobacillus gasseri resulted in attenuation of the SHT-induced CYP1A2 inhibition, but not CYP2E1 induction, suggesting that changes in the chemical composition of SHT through fermentation can affect the inhibition of CYP1A2 activity.Food Chemistry 01/2013; 136(2):450-7. · 3.65 Impact Factor -
Article: Pharmacometabolomic Approach to Predict QT Prolongation in Guinea Pigs.
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ABSTRACT: Drug-induced torsades de pointes (TdP), a life-threatening arrhythmia associated with prolongation of the QT interval, has been a significant reason for withdrawal of several medicines from the market. Prolongation of the QT interval is considered as the best biomarker for predicting the torsadogenic risk of a new chemical entity. Because of the difficulty assessing the risk for TdP during drug development, we evaluated the metabolic phenotype for predicting QT prolongation induced by sparfloxacin, and elucidated the metabolic pathway related to the QT prolongation. We performed electrocardiography analysis and liquid chromatography-mass spectroscopy-based metabolic profiling of plasma samples obtained from 15 guinea pigs after administration of sparfloxacin at doses of 33.3, 100, and 300 mg/kg. Principal component analysis and partial least squares modelling were conducted to select the metabolites that substantially contributed to the prediction of QT prolongation. QTc increased significantly with increasing dose (r = 0.93). From the PLS analysis, the key metabolites that showed the highest variable importance in the projection values (>1.5) were selected, identified, and used to determine the metabolic network. In particular, cytidine-5'-diphosphate (CDP), deoxycorticosterone, L-aspartic acid and stearic acid were found to be final metabolomic phenotypes for the prediction of QT prolongation. Metabolomic phenotypes for predicting drug-induced QT prolongation of sparfloxacin were developed and can be applied to cardiac toxicity screening of other drugs. In addition, this integrative pharmacometabolomic approach would serve as a good tool for predicting pharmacodynamic or toxicological effects caused by changes in dose.PLoS ONE 01/2013; 8(4):e60556. · 4.09 Impact Factor -
Article: Cytochrome P450-mediated herb-drug interaction potential of Galgeun-tang.
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ABSTRACT: We evaluated the herb-drug interaction potential of Galgeun-tang (GGT) extracts, mediated by cytochrome P450 (CYP) inhibition/induction. Further, the effects of fermentation on the CYPmediated herb-drug interaction potential of GGT extracts were determined. As measured by LCESI/ MS/MS, GGT extracts (0-300 μg/mL) showed no inhibitory activity toward eight CYP isoforms (1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4) in pooled human liver microsomes, suggesting that GGT may have low potential for herb-drug interactions mediated by CYP inhibition. Hepatic CYP expression and activity in rats treated with GGT extracts twice per day for 1 week was examined. Among the tested CYP isoforms (1A1, 1A2, 1B1, 2B1, 2C11, 2E1, 3A1, 3A2, and 4A1), CYP1B1 and 4A1 were increased by GGT extracts. Hepatic activities of 7-ethoxyresorufin-O-deethylase, 7-pentoxyresorufin-Odepentylase, and chlorzoxazone 6-hydroxylase, but not midazolam hydroxylase were also elevated. These results raise the possibility that GGT extracts may increase the toxicity of environmental toxicants through the elevating CYP-dependent metabolic activation. Interestingly, the increases in CYP1B1 and CYP4A1 levels, and 7-ethoxyresorufin-O-deethylase, 7-pentoxyresorufin-O-depentylase, and chlorzoxazone 6-hydroxylase activities were attenuated by fermentation of GGT extract using Lactobacillus plantarum KFRI 402, but not 144. Further studies are needed to identify the CYP regulatory component(s) from GGT and determination its metabolism.Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 10/2012; · 2.99 Impact Factor -
Article: Globular adiponectin inhibits ethanol-induced apoptosis in HepG2 cells through heme oxygenase-1 induction.
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ABSTRACT: Hepatocellular apoptosis is an essential pathological feature of alcoholic liver disease. Adiponectin, an adipokine predominantly secreted from adipose tissue, has been shown to play beneficial roles in alcoholic liver disease against various inflammatory and pro-apoptotic molecules. However, the effects of adiponectin on ethanol-induced apoptosis in liver cells are largely unknown. Herein, we investigated the role of globular adiponectin (gAcrp) in the prevention of ethanol-induced apoptosis and further tried to decipher the potential mechanisms involved. In the present study, we demonstrated that gAcrp significantly inhibits both ethanol-induced increase in Fas ligand expression and activation of caspase-3 in human hepatoma cell lines (HepG2 cells), suggesting that gAcrp plays a protective role against ethanol-induced apoptosis in liver cells. This protective effect of gAcrp was mediated through adiponectin receptor R1 (adipoR1). Further, globular adiponectin treatment caused induction of heme oxygenase-1 (HO-1) through, at least in part, nuclear factor (erythroid-derived 2)-like 2, (Nrf2) signaling. Treatment with SnPP, a pharmacological inhibitor of HO-1, and knockdown of HO-1 with small interfering RNA (siRNA) restored caspase-3 activity suppressed by gAcrp, indicating a critical role of HO-1 in mediating the protective role of gAcrp in ethanol-induced apoptosis in liver cells. In addition, carbon monoxide, a byproduct obtained from the catabolism of free heme was found to contribute to the anti-apoptotic effect of adiponectin. In conclusion, these data demonstrated that globular adiponectin prevents ethanol-induced apoptosis in HepG2 cells via HO-1 induction and revealed a novel biological response of globular adiponectin in the protection of liver injury from alcohol consumption.Biochemical pharmacology 07/2012; 84(7):974-83. · 4.25 Impact Factor -
Article: Quantitative determination of aceclofenac and its three major metabolites in rat plasma by HPLC-MS/MS.
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ABSTRACT: We developed a method for the simultaneous quantification of aceclofenac and its three major metabolites in rat plasma. After protein precipitation with acetonitrile including flufenamic acid as an internal standard (IS), aceclofenac, diclofenac, 4'-hydroxyaceclofenac, 4'-hydroxydiclofenac, and the IS were chromatographed on a reverse-phase C18 analytical column. The isocratic mobile phase of acetonitrile/0.1% formic acid (aq; 9:1 [v/v]) was eluted at 0.3 mL/min. Quantification was performed on a triple-quadrupole mass spectrometer using electrospray ionization, and the ion transitions were monitored in selective reaction-monitoring mode. The coefficient of variation in the assay precision was less than 8%, and the accuracy was 92-103%. This method was successfully used to measure the concentrations of aceclofenac and its three major metabolites in rat plasma following the oral administration of a single 20 mg/kg oral dose of aceclofenac.Journal of Separation Science 07/2012; 35(17):2219-22. · 2.73 Impact Factor
