Flavokawain A inhibits Cytochrome P450 in in vitro metabolic and inhibitory investigations.

【作者】 Lifeng Niu a, Lina Ding a, Chunyun Lu a, Feifei Zuo a, Ke Yao a, Shaobo Xu a, Wen Li a,

Donghua Yang b, Xia Xu

【期刊名】 Journal of Ethnopharmacology

【影响因子】 2014年:2.9

【作者单位】 School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, PR China

【年，卷(期)：页码】191 (2016) 350–359

【关键词】 Flavokawain A；Cytochrome P450；Metabolism；Rat liver microsome；Molecular docking

【摘要】Ethnopharmacological relevance: Flavokawain A, the major chalcone in kava extracts, was served as beverages for informal social occasions and traditional ceremonials in most South Pacific islands. It exhibited strong antiproliferative and apoptotic effects against human prostate and urinary bladder cancer cells.

Aim of the study: The current study was purposed to investigate the interaction between Flavokawain Aand Cytochrome P450, including the inhibitory effects of Flavokawain A on predominant CYP450 isotypes and further clarified the inhibitory mechanism of FKA on CYP450 enzymes. Besides, study about identifying the key CYP450 isotypes responsible for the metabolism of FKA was also performed.Materials and methods: In this study, probe-based assays with rat liver microsome system were used tocharacterize the inhibitory effects of FKA. Molecular docking study was performed to further explore thebinding site of FKA on CYP450 isoforms. In addition, chemical inhibition experiments using specificinhibitors (a-naphthoflavone, quinidine, sulfamethoxazde, ketoconazole, omeprazole) were performed toclarify the individual CYP450 isoform that are responsible for the metabolism of FKA.

Results: FKA showed significant inhibition on CYP1A2, CYP2D1, CYP2C6 and CYP3A2 activities with IC50values of 102.23, 20.39, 69.95, 60.22 μmol/L, respectively. The inhibition model was competitive, mixedinhibition, uncompetitive, and noncompetitive for CYP1A2, CYP2D1, CYP2C6 and CYP3A2 enzymes.Molecular docking study indicated the ligand-binding conformation of FKA in the active site of CYP450 isoforms. The chemical inhibition experiments showed that the metabolic clearance rate of FlavokawainA decreased to 19.84%, 50.38%, and 67.02% of the control in the presence of ketoconazole, sulfamethoxazde and a-naphthoflavone.

Conclusion: The study showed that Flavokawain A has varying inhibitory effect on CYP450 enzymes and CYP3A2 was the principal CYP isoform contributing to the metabolism of Flavokawain A. Besides, CYP2C6 and CYP1A2 isoforms also play important roles in the metabolism of FKA. Our results provided a basis for better understanding the biotransformation of FKA and prediction of drug-drug interaction of FKA.

【全文链接】https://www.ncbi.nlm.nih.gov/pubmed/?term=Flavokawain+A+inhibits+Cytochrome+P450+in+in+vitro+metabolic+and+inhibitory+investigations