Journal of Microbiology and Biotechnology

The Korean Society for Microbiology and Biotechnology (한국미생물·생명공학회)
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Effect of TSHAC on Human Cytochrome P450 Activity, and Transport Mediated by P-Glycoprotein

  • Im, Yelim (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University) ;
  • Kim, Yang-Weon (Department of Emergency Medicine, Busan Paik Hospital, Inje University College of Medicine) ;
  • Song, Im-Sook (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University) ;
  • Joo, Jeongmin (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University) ;
  • Shin, Jung-Hoon (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University) ;
  • Wu, Zhexue (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University) ;
  • Lee, Hye Suk (College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea) ;
  • Park, Ki Hun (Division of Applied Life Science, Gyeongsang National University) ;
  • Liu, Kwang-Hyeon (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University)
  • Received : 2012.09.06
  • Accepted : 2012.09.12
  • Published : 2012.12.28
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Abstract

TSAHC [4'-(p-toluenesulfonylamido)-4-hydroxychalcone] is a promising antitumorigenic chalcone compound, especially against TM4SF5 (four-transmembrane L6 family member 5)-mediated hepatocarcinoma. We evaluated the potential of TSAHC to inhibit the catalytic activities of nine cytochrome P450 isoforms and of P-glycoprotein (P-gp). The abilities of TSAHC to inhibit phenacetin O-deethylation (CYP1A2), coumarin 6-hydroxylation (CYP2A6), bupropion hydroxylation (CYP2B6), amodiaquine N-deethylation (CYP2C8), diclofenac 4-hydroxylation (CYP2C9), omeprazole 5-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), chlorzoxazone 6-hydroxylation (CYP2E1), and midazolam 1'-hydroxylation (CYP3A) were tested using human liver microsomes. The P-gp inhibitory effect of TSAHC was assessed by [$^3H$]digoxin accumulation in the LLCPK1-MDR1 cell system. TSAHC strongly inhibited CYP2C8, CYP2C9, and CYP2C19 isoform activities with $K_i$ values of 0.81, 0.076, and $3.45{\mu}M$, respectively. It also enhanced digoxin accumulation in a dose-dependent manner in the LLCPK1-MDR1 cells. These findings indicate that TSAHC has the potential to inhibit CYP2C isoforms and P-gp activities in vitro. TSAHC might be used as a nonspecific inhibitor of CYP2C isoforms based on its negligible inhibitory effect on other P450 isoforms such as CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2E1, and CYP3A.

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