tailieunhanh - báo cáo hóa học:" Bioactivities of berberine metabolites after transformation through CYP450 isoenzymes"

Tuyển tập các báo cáo nghiên cứu về hóa học được đăng trên tạp chí sinh học đề tài : Bioactivities of berberine metabolites after transformation through CYP450 isoenzymes | Li et al. Journal of Translational Medicine 2011 9 62 http content 9 1 62 JOURNAL OF TRANSLATIONAL MEDICINE RESEARCH Open Access Bioactivities of berberine metabolites after transformation through CYP450 isoenzymes 1 t 11 1 1 1 1 11 Yi Li Gang Ren Yan-Xiang Wang Wei-Jia Kong Peng Yang Yue-Ming Wang Ying-Hong Li Hong Yi Zhuo-Rong Li1 Dan-Qing Song1 and Jian-Dong Jiang1 2 Abstract Background Berberine BBR is a drug with multiple effects on cellular energy metabolism. The present study explored answers to the question of which CYP450 Cytochrome P450 isoenzymes execute the phase-I transformation for BBR and what are the bioactivities of its metabolites on energy pathways. Methods BBR metabolites were detected using LC-MS MS. Computer-assistant docking technology as well as bioassays with recombinant CYP450s were employed to identify CYP450 isoenzymes responsible for BBR phase-I transformation. Bioactivities of BBR metabolites in liver cells were examined with real time RT-PCR and kinase phosphorylation assay. Results In rat experiments 4 major metabolites of BBR berberrubine M1 thalifendine M2 demethyleneberberine M3 and jatrorrhizine M4 were identified in rat s livers using LC-MS MS liquid chromatography-tandem mass spectrometry . In the cell-free transformation reactions M2 and M3 were detectable after incubating BBR with rCYP450s or human liver microsomes however M1 and M4 were below detective level. CYP2D6 and CYP1A2 played a major role in transforming BBR into M2 CYP2D6 CYP1A2 and CYP3A4 were for M3 production. The hepatocyte culture showed that BBR was active in enhancing the expression of insulin receptor InsR and low-density-lipoprotein receptor LDLR mRNA as well as in activating AMP-activated protein kinase AMPK . BBR s metabolites M1-M4 remained to be active in up-regulating InsR expression with a potency reduced by 50-70 LDLR mRNA was increased only by M1 or M2 but not M3 and M4 with an activity level 35 or 26 of that of BBR .