Potent inhibitory effect of alpha-viniferin on human cytochrome P450.
α-Viniferin isolated from Caragana chamlagu is a trimer of resveratrol, and has several biological activities, which include anti-inflammatory, anti-oxidant, anti-arthritis, and anti-tumor activities. Herb-drug interactions are the source of the most harmful complications in patients coadministered herbal and modern medicines, and are caused by modulation of the activities of drug metabolizing enzymes. Here, the authors investigated the inhibitory effects of α-viniferin on the activities of 9 human cytochrome P450 (CYP) isoforms using a cocktail of probe substrates and LC-MS/MS in pooled human liver microsomes (HLMs). α-Viniferin strongly inhibited 7 of the 9 CYP isoforms (except CYP2A6 and CYP2E1). Furthermore, α-viniferin strongly inhibited CYP2C19-mediated omeprazole 5-hydroxylation and CYP3A4-catalyzed midazolam 1-hydroxylation with IC50 values of 0.93 and 1.2 μM, respectively. α-Viniferin strongly inhibited the activities of these two CYPs dose dependently, but not time-dependently. Lineweaver-Burk plots and secondary plots indicated a typical pattern of mix-mode inhibition for CYP2C19 and 3A4. This is the first investigation conducted on the inhibitory effect of α-viniferin on CYP2C19 and 3A4 in HLMs to predict a potential herb-drug interaction.
College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701, South Korea.
Juhee
J
Sim
College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701, South Korea.
Hae Wring
HW
Jang
College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701, South Korea.
Min
M
Song
College of Pharmacy, Yeungnam University, Gyeongsan 712-749, South Korea.
Ji Hyang
JH
Kim
College of Pharmacy, Yeungnam University, Gyeongsan 712-749, South Korea.
Seung Ho
SH
Lee
College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701, South Korea. Electronic address: sangkyu@knu.ac.kr.
Sangkyu
S
Lee
D001572:Benzofurans / Q000494:pharmacology*; D065729:Cytochrome P-450 CYP2C9 / Q000378:metabolism; D065688:Cytochrome P-450 CYP2C9 Inhibitors / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D041743:Herb-Drug Interactions; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D053719:Tandem Mass Spectrometry
D001572:Benzofurans; D065688:Cytochrome P-450 CYP2C9 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; C064176:alpha-viniferin; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
Alpha-viniferin; Cytochrome P450; Human liver microsomes; Inhibition; Interaction