In vitro inhibition of human cytochrome P450 by cudratricusxanthone A.
Cudratricusxanthone A (CTXA) isolated from the roots of Cudrania tricuspidata Bureau (Moraceae) has several biological activities, including hepatoprotective, neuroprotective, anti-inflammatory, monoamine oxidase inhibitory, and antithrombotic activities. In this study, we investigated the potential herb-drug interaction of CTXA and nine cytochrome P450 (CYP) isoforms in pooled human liver microsomes (HLMs) using a cocktail probe assay. CTXA reversibly inhibited the CYP1A2-catalyzed phenacetin O-deethylation, CYP2C8-catalyzed paclitaxel 6-hydroxylation, and CYP2C9-catalyzed diclofenac 4'-hydroxylation with half-maximal inhibitory concentration (IC50) values of 3.9, 4.7, and 2.9 µM, respectively. The IC50 values did not change under different preincubation conditions. CTXA showed marked dose-dependent, but not time-dependent, inhibition of CYP1A2 and 2C9 activities in HLMs. Dixon plots showed typical competitive inhibition of CYP1A2 and CYP2C9 with Ki values of 1.3 and 1.5 µM, respectively. Further, CTXA inhibited CYP2C8 in a non-competitive manner with a Ki value of 2.2 µM. Our results showed that CTXA reversibly inhibits CYP1A2, 2C8, and 2C9.
College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Republic of Korea.
Juhee
J
Sim
College of Pharmacy, Keimyung University, Republic of Korea.
Eunhwa
E
Choi
College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Republic of Korea.
You-Mie
YM
Lee
College of Pharmacy, Keimyung University, Republic of Korea. Electronic address: gsjeong@kmu.ac.kr.
Gil-Saeng
GS
Jeong
College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Republic of Korea. Electronic address: sangkyu@knu.ac.kr.
Sangkyu
S
Lee
D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D002853:Chromatography, Liquid; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065727:Cytochrome P-450 CYP2C8 / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9 / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology*; D041743:Herb-Drug Interactions; D006801:Humans; D006900:Hydroxylation; D020128:Inhibitory Concentration 50; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D029586:Moraceae / Q000737:chemistry; D018517:Plant Roots / Q000737:chemistry; D053719:Tandem Mass Spectrometry; D044004:Xanthones / Q000494:pharmacology*
D065607:Cytochrome P-450 Enzyme Inhibitors; D044004:Xanthones; C533013:cudratricusxanthone A; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D019388:Cytochrome P-450 CYP1A2; D065727:Cytochrome P-450 CYP2C8
Cudratricusxanthone A; Cytochrome P450; Human liver microsomes; Inhibition; Interaction