title: Inhibitory effects of deoxypodophyllotoxin from Anthriscus sylvestris on human CYP2C9 and CYP3A4.
abstract: 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.
authors: Doping Control Center, Korea Institute of Science and Technology, Chungryang, Seoul 130-650, Korea.
authors: Sang Kyu
authors: SK
authors: Lee
authors: Yoon
authors: Y
authors: Kim
authors: Changbae
authors: C
authors: Jin
authors: Seung Ho
authors: SH
authors: Lee
authors: Mi Jeong
authors: MJ
authors: Kang
authors: Tae Cheon
authors: TC
authors: Jeong
authors: Seo Young
authors: SY
authors: Jeong
authors: Dong-Hyun
authors: DH
authors: Kim
authors: Hye Hyun
authors: HH
authors: Yoo
mesh_terms: 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
chemical_list: 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