Inhibitory effects of deoxypodophyllotoxin from Anthriscus sylvestris on human CYP2C9 and CYP3A4.
Deoxypodophyllotoxin (DPT) is a bioactive compound of Anthriscus sylvestris (Apiaceae). In the present study, the inhibition of cytochrome P450 (CYP) by DPT was evaluated in human liver microsomes (HLM) and the baculovirus-insect cell-expressed human CYPs using a cocktail probe assay. When a mixture of specific CYP substrates was incubated with DPT in HLM, CYP2C9-catalyzed diclofenac 4-hydroxylation and CYP3A4-catalyzed midazolam 1-hydroxylation were strongly inhibited by DPT, with IC (50) values of 6.3 and 9.2 microM, respectively. The Lineweaver-Burke plots for the inhibition of CYP2C9 and CYP3A4 in HLM and baculovirus-insect cell-expressed human CYPs were consistent with a competitive type of inhibition. From these results, DPT was characterized to be a competitive inhibitor of CYP2C9 and CYP3A4, with K(i) values of 3.5 and 10.8 microM in HLM and 24.9 and 3.5 microM in baculovirus-insect cell-expressed human CYPs, respectively.
Lee
Sang Kyu
SK
Doping Control Center, Korea Institute of Science and Technology, Chungryang, Seoul 130-650, Korea.
Kim
Yoon
Y
Jin
Changbae
C
Lee
Seung Ho
SH
Kang
Mi Jeong
MJ
Jeong
Tae Cheon
TC
Jeong
Seo Young
SY
Kim
Dong-Hyun
DH
Yoo
Hye Hyun
HH
D019661:Apiaceae; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004353:Drug Evaluation, Preclinical; D004365:Drugs, Chinese Herbal; D006801:Humans; D008862:Microsomes, Liver; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000494:pharmacology
D065692:Cytochrome P-450 CYP3A Inhibitors; D004365:Drugs, Chinese Herbal; C014451:deoxypodophyllotoxin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D011034:Podophyllotoxin