Effects Of Strychnine Hydrochloride And Its Combination With Glycyrrhetinic Acid, Liquiritin On Rat Liver CYP450 Enzymes MRNA Expression And Enzyme Activity

The activity of mammalian hepatic cytochrome P450 enzymes(CYPs) can be effected by both endogenous factors and foreign compounds. In order to minimize potential drug side effects, expecially the dugs with a narrow therapeutic window, it is important to ascertain the effect of co-administration on CYPs activities.Strychnos nux-vomica L.,which the main components are strychnine and brucine, has been frequently used in traditional Chinese medicine to treat joint pain, arthritic and rheumatic diseases. Because of its highly acute toxicity, Strychnos nux-vomica L. was customarily used with Glycyrrhizae radix to decrease its toxicity, but the detoxication mechanism was unclear yet today.In this work, The activities of four CYP450 enzymes(CYP3A,1A2,2E1 and 2C) and the mRNA expression levels of CYP1A2,2E1,2C11 and 3A1 in rat liver were determined after Wistar rats were orally administered by strychnine hydrochloride(SH) at three dosage levels(0.1mg/kg/day,0.3mg/kg/day and 0.9mg/kg/day) and the high dose of SH combined with glycyrrhetinic acid(GA,25mg/kg/day) or liquiritin(LQ, (20mg/kg/day), respectively for 7 consecutive days. In the current study, compared with the control, the mRNA expression of CYP3A1,1A2 and 2E1 were obviously increased at the high dose of SH group, whereas reverse changes were observed for the mRNA expression of CYP3A1 and 2E1 at the coadministration groups of (SH+GA) and (SH+LQ) as compared with the high dose of SH group. On the other hand, the high dose of SH caused a significant increase in CYP2E1 activity (P<0.05), whereas caused significant decrease in the activities of CYP2C, CYP3A and CYP1A2 as compared with the control. Meanwhile, the coadministration of (SH+GA) caused a significant decrease in CYP2E1 activity and an obvious decrease in CYP3A activity (P>0.05), whereas caused significant increase in CYP1A2 and CYP2C activities as compared with the high dose of SH group. In addition, the coadministration of (SH+LQ) significantly decreased CYP2E1 activity and obviously decreased CYP3A activity (P>0.05).Our results demonstrated Glycyrrhetinic acid can weaken the induction of CYP2E1 activity, it may reduce the chance that carcinogenic substances and the former first transformed into carcinogens and toxic poison caused by strychnine hydrochloride. Meanwhile, glycyrrhetinic acid can decrease the inhibition of CYP2C activity, and thus weaken the unexpected expansion of efficacy, which due to SH. Taken together, GA and LQ may have drug-drug interactions with SH, which can affect the enzyme activity of four CYPs, which might provide some experimental evidence in the compatibility of SH in clinical.