title: Effect of TSHAC on human cytochrome P450 activity, and transport mediated by P-glycoprotein.
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 (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 microM, 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.
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Korea.
authors.forename: Yelim
authors.initials: Y
authors.lastname: Im
authors.forename: Yang-Weon
authors.initials: YW
authors.lastname: Kim
authors.forename: Im-Sook
authors.initials: IS
authors.lastname: Song
authors.forename: Jeongmin
authors.initials: J
authors.lastname: Joo
authors.forename: Jung-Hoon
authors.initials: JH
authors.lastname: Shin
authors.forename: Zhexue
authors.initials: Z
authors.lastname: Wu
authors.forename: Hye Suk
authors.initials: HS
authors.lastname: Lee
authors.forename: Ki Hun
authors.initials: KH
authors.lastname: Park
authors.forename: Kwang-Hyeon
authors.initials: KH
authors.lastname: Liu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D002599:Chalcone / Q000031:analogs & derivatives* / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004077:Digoxin / Q000378:metabolism; D004347:Drug Interactions; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D008954:Models, Biological; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: C540441:4'-(4-toluenesulfonylamido)-4-hydroxychalcone; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D013449:Sulfonamides; D002599:Chalcone; D004077:Digoxin; D003577:Cytochrome P-450 Enzyme System