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KMID : 0545120120220121659
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Journal of Microbiology and Biotechnology
2012 Volume.22 No. 12 p.1659 ~ p.1664
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Effect of TSHAC on Human Cytochrome P450 Activity, and Transport Mediated by P-Glycoprotein
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Im Ye-Lim
Kim Yang-Weon
Song Im-Sook
Joo Jeong-Min
Shin Jung-Hoon
Zhexue Wu
Lee Hye-Suk
Park Ki-Hun
Liu Kwang-Hyeon
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Abstract
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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 (Pgp). The abilities of TSAHC to inhibit phenacetin Odeethylation (CYP1A2), coumarin 6-hydroxylation (CYP2A6), bupropion hydroxylation (CYP2B6), amodiaquine Ndeethylation (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 Ki values of 0.81, 0.076, and 3.45 μM, 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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KEYWORD
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TSAHC, cytochrome P450s, P-glycoprotein, human liver microsomes, drug interactions
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