title: Effects of Radix Astragali and Radix Rehmanniae, the components of an anti-diabetic foot ulcer herbal formula, on metabolism of model CYP1A2, CYP2C9, CYP2D6, CYP2E1 and CYP3A4 probe substrates in pooled human liver microsomes and specific CYP isoforms.
abstract: The present study investigated the effects of Radix Astragali (RA) and Radix Rehmanniae (RR), the major components of an anti-diabetic foot ulcer herbal formula (NF3), on the metabolism of model probe substrates of human CYP isoforms, CYP1A2, CYP2C9, CYP2D6, CYP2E1 and CYP3A4, which are important in the metabolism of a variety of xenobiotics. The effects of RA or RR on human CYP1A2 (phenacetin O-deethylase), CYP2C9 (tolbutamide 4-hydroxylase), CYP2D6 (dextromethorphan O-demethylase), CYP2E1 (chlorzoxazone 6-hydroxylase) and CYP3A4 (testosterone 6β-hydroxylase) activities were investigated using pooled human liver microsomes. NF3 competitively inhibited activities of CYP2C9 (IC(50)=0.98mg/ml) and CYP3A4 (IC(50)=0.76mg/ml), with K(i) of 0.67 and 1.0mg/ml, respectively. With specific human CYP2C9 and CYP3A4 isoforms, NF3 competitively inhibited activities of CYP2C9 (IC(50)=0.86mg/ml) and CYP3A4 (IC(50)=0.88mg/ml), with K(i) of 0.57 and 1.6mg/ml, respectively. Studies on RA or RR individually showed that RR was more important in the metabolic interaction with the model CYP probe substrates. RR dose-dependently inhibited the testosterone 6β-hydroxylation (K(i)=0.33mg/ml) while RA showed only minimal metabolic interaction potential with the model CYP probe substrates studied. This study showed that RR and the NF3 formula are metabolized mainly by CYP2C9 and/or CYP3A4, but weakly by CYP1A2, CYP2D6 and CYP2E1. The relatively high K(i) values of NF3 (for CYP2C9 and CYP3A4 metabolism) and RR (for CYP3A4 metabolism) would suggest a low potential for NF3 to cause herb-drug interaction involving these CYP isoforms.
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China.
authors.forename: Penelope M Y
authors.initials: PM
authors.lastname: Or
authors.forename: Francis F Y
authors.initials: FF
authors.lastname: Lam
authors.forename: Y W
authors.initials: YW
authors.lastname: Kwan
authors.forename: C H
authors.initials: CH
authors.lastname: Cho
authors.forename: C P
authors.initials: CP
authors.lastname: Lau
authors.forename: H
authors.initials: H
authors.lastname: Yu
authors.forename: G
authors.initials: G
authors.lastname: Lin
authors.forename: Clara B S
authors.initials: CB
authors.lastname: Lau
authors.forename: K P
authors.initials: KP
authors.lastname: Fung
authors.forename: P C
authors.initials: PC
authors.lastname: Leung
authors.forename: John H K
authors.initials: JH
authors.lastname: Yeung
mesh_terms: D027883:Astragalus Plant; D027885:Astragalus propinquus; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D017719:Diabetic Foot / Q000188:drug therapy*; D004341:Drug Evaluation; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology; D032267:Rehmannia / Q000737:chemistry*
chemical_list: D004365:Drugs, Chinese Herbal; D010936:Plant Extracts; C027492:Huang Qi; D006899:Mixed Function Oxygenases; D019392:Cytochrome P-450 CYP2E1; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6