Inhibitory effects of schisandrin A and schisandrin B on CYP3A activity.
Our aim was to investigate the inhibitory effects of schisandrin A and schisandrin B on cytochrome P450 (CYP3A) activity in rat liver microsomes and the mechanism of this interaction. 1'-Hydroxy midazolam and midazolam 1-hydroxylation catalyzed by CYP3A were analyzed by high performance liquid chromatography (HPLC). Results showed that schisandrin A and schisandrin B inhibited CYP3A activity with IC(50) values of 6.60 and 5.51 microM and K(i) values of 5.83 and 4.24 microM, respectively. A dilution assay plot of each inhibitor gave a slope value of up to 91% that of the control samples. The inactivation of CYP3A activity by schisandrin A and schisandrin B was found to be both time-and concentration-dependent (schisandrin A: K(I) = 4.51 microM, K(inact) = 0.134/min; schisandrin B: K(I) = 3.01 microM, K(inact) = 0.112/min). We conclude that the inhibition of CYP3A activity in rat liver microsomes by schisandrin A and schisandrin B is mostly attributed to a mixed noncompetitive and complete inhibition.
Li
W L
WL
Department of Clinical Pharmacology, Wuhan General Hospital of Guangzhou Command, Wuhan, P.R. China.
Xin
H W
HW
Su
M W
MW
Xiong
L
L
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D034242:Cyclooctanes / Q000008:administration & dosage / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D017705:Lignans / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D008874:Midazolam / Q000378:metabolism; D011083:Polycyclic Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D034242:Cyclooctanes; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D017705:Lignans; D011083:Polycyclic Compounds; C015499:schizandrin B; C034734:schizandrin A; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam