Studies On The Effect Of Schisandra Chinensis Extract And Gomisin A On Cyclophosphamide Metabolism

Schisandra chinensis（S.chinensis）has been used for thousands years in China with unique tonic effects including calming,nourishing the kidney,tonifying qi,astringenting and promoting the production of body fluids.With significant protective effect on liver,kidney and nervous system,schisandrae lignans have been recognized as the main bioactive components of S.chinensis.S.chinensis extract（SCE）has been found with multifaceted effects on CYP3A activity:it was found that SCE possessed inhibitory effect on CYP3A activity at single dose while exhibiting inductive effect when administrated repetitively.Cyclophosphamide（CTX）is commonly used in clinical field as an anticancer agent as well as a potent immunosuppressant.The majority of CTX is activated by CYP2B6 into effective constituent phosphoramide mustard（main-chain metabolism）.However,CTX is prone to cause severe toxicity due to its CYP3A metabolite chloroacetaldehyde（CAA,side-chain metabolite）.In this study,the chemo-preventive effects of SCE on CTX-induced toxicity were discussed by investigating the drug-drug interactions（DDIs）between SCE（as well as its main bioactive component gomisin A）and CTX.When incubated with human liver microsomes,SCE inhibited CYP3A activity concentration dependently with IC50 value of 7.0μg/mL.When administrated to rats,it was found that single-dose SCE（0.75 g/kg）strongly inhibited CYP3A-mediated metabolic pathway of CTX.However,repetitive SCE administration showed a minor inhibitory effect on CYP3A-mediated CTX metabolism.Parallel toxicity and oxidation investigations showed that the single-dose SCE co-administration（0.75 g/kg）significantly decreased oxidative stress levels in tissues of CTX-treated rats and attenuated CTX-induced injuries by reducing rat plasma BUN,Cr levels,liver AST activity and MDA content in liver,kidney and brain.The GSH/GSSG ratios in liver and brain were also increased when rats were pre-treated with SCE.Gom A is the enriched characteristic active component of S.chinensis.In this study,Gom A was found to be a competitive CYP3A inhibitor（reversible inhibitor）with K_i value of 1.10μM,as well as a time-dependent inhibitor with KI of 0.35 μM and k_inact of 1.96 min^-1.The CYP3A in rat liver microsomes did not regain activity within 12 h after Gom A administration,which suggested CYP3A inactivation.What’s more,rat hepatic CYP3A mRNA expression experienced a significant increase 24 h after Gom A administration,the inductive effect last for more than 3 d.It was therefore reasonable to explain the bidirectional effect of Gom A on CYP3A-mediated CTX metabolism:the CYP3A-mediated CTX metabolism was significantly inhibited in the 0.5 h-and 6 h-pretreatment rat groups while promoted in the 24 h-and 72 h-pretreatment groups.The present study suggested that SCE and Gom A possess chemo-preventive effects against CTX toxicity by blocking CYP3A-mediated metabolism and reducing CAA production,in addition to their previous recognized protective effects on liver,kidney and nervous system.Also,the combined use of S.chinensis preparation or drugs containing Gom A as the main component with CTX needed to be addressed for better clinical intervention.