[Effects of Schisandra chinensis (Wuweizi) constituents on the activity of hepatic microsomal CYP450 isozymes in rats detected by using a cocktail probe substrates method]

Abstract

Effects of constituents from Schisandra chinensis (Wuweizi) on six liver microsomal CYP450 isozymes (CYP1A2, CYP2C6, CYP2C11, CYP2D2, CYP2E1 and CYP3A1/2) were studied in rats in vivo and in vitro. The in vitro incubation was conducted using liver microsomes of rats after multiple dosing of alcoholic/water extract from Schisandra chinensis. A HPLC-MS method was applied to determine the metabolites formation of six CYP450s probe substrates (phenacetin-CYP1A2, dextromethorphan-CYP2D2, diclofenac sodium-CYP2C6, mephenytoin-CYP2C11, chlorzoxazone-CYP2E1 and midazolam-CYP3A1/2) in rat liver microsomal incubations. The activity of CYP450 isozymes were represented by the formation of metabolites. Alcoholic extract of Schisandra chinensis (28-120 microg x mL(-1)) showed significant inhibitory effect on six CYP450 isozymes to a certain extent in vitro. Multiple dosing of Schisandra chinensis alcoholic extract (1.5 g x kg(-1), qd x 7d) had significant induction on CYP2E1 and CYP3A1/2, inhibition on CYP2D2 and CYP2C11, and no effect on CYP2C6 and CYP1A2. Water extract of Schisandra chinensis (100-500 microg x mL(-1)) also exhibited inhibition on the activity of CYP450 isozymes in vitro, whereas multiple administrations (1.5 g x kg(-1), qd x 7d) had significant induction of CYP2E1 and inhibition on CYP2D2, no effect on CYP2C6, CYP3A1/2, CYP1A2 or CYP2C11. The results suggested that the constituents from Schisandra chinensis exhibited the inhibition and induction on six rat liver microsomal CYP450 isozymes to a certain extent in vivo and in vitro. The possibility of interaction between Schisandra chinensis and coadministrative drugs will be considered base on the levels and subtype of CYP450 involved in the drug metabolism.