In vitro assessment of the glucose-lowering effects of berberrubine-9-O-β-D-glucuronide, an active metabolite of berberrubine  

作　　者：Na YANG Run-bin SUN Xing-long CHEN Le ZHEN Chun GE Yu-qing ZHAO Jun HE Jian-liang GENG Jia-hua GUO Xiao-yi YU Fei FEI Si-qi FENG Xuan-xuan ZHU Hong-bo WANG Feng-hua FU Ji-ye AA Guang-ji WANG 

机构地区：[1]Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China [2]State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China [3]Department of Pharmacology, Clinical Research Institute of Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing 210009, China [4]Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Pharmacy School at Yantai University, Yantai 264005, China

出　　处：《Acta Pharmacologica Sinica》2017年第3期351-361,共11页中国药理学报（英文版）

基　　金：Acknowledgements This study was financially supported by the National Natural Science Foundation of China （No_ 81573495, 81530098）, the Key Technology Projects of China ＂Creation of New Drugs＂ （No_ 2015ZX09501001）, the Project for Jiangsu Province Key Lab of Drug Metabolism and Pharmacokinetics （No BM2012012） and the Project of the University Collaborative Innovation Center of Jiangsu Province （Modern Chinese Medicine Center and Biological Medicine Center）.

摘　　要：Berberrubine （BRB） is the primary metabolite of berberine （BBR） that has shown a stronger glucose-lowering effect than BBR in vivo. On the other hand, BRB is quickly and extensively metabolized into berberrubine-9-O-β-D-glucuronide （BRBG） in rats after oral administration. In this study we compared the pharmacokinetic properties of BRB and BRBG in rats, and explored the mechanisms underlying their glucose-lowering activities. C57BL/6 mice with HFD-induced hyperglycemia were administered BRB （50 mg·kg^-1·d^-1, ig） for 6 weeks, which caused greater reduction in the plasma glucose levels than those caused by BBR （120 mg·kg^-1·d^-1） or BRB （25 mg·kg^-1·d^-1）. In addition, BRB dose-dependently decreased the activity of α-glucosidase in gut of the mice. After oral administration of BRB in rats, the exposures of BRBG in plasma at 3 different dosages （10, 40, 80 mg/kg） and in urine at different time intervals （0-4, 4-10, 10-24 h） were dramatically greater than those of BRB. In order to determine the effectiveness of BRBG in reducing glucose levels, we prepared BRBG from the urine pool of rats, and identified and confirmed it through LC-MS-IT-TOF and NMR spectra. In human normal liver cell line 1_-02 in vitro, treatment with BRB or BRBG （5, 20, 50 pmol/L） increased glucose consumption, enhanced glycogenesis, stimulated the uptake of the glucose analog 2-NBDG, and modulated the mRNA levels of glucose-6-phosphatase and hexokinase. However, both BBR and BRB improved 2-NBDG uptake in insulin-resistant L-02 cells, while BRBG has no effect. In conclusion, BRB exerts a stronger glucose-lowering effect than BBR in HFD-induced hyperglycemia mice. Although BRB significantly stimulated the insulin sensitivity and glycolysis in vitro, BRBG may have a greater contribution to the glucose-lowering effect because it has much greater system exposure than BRB after oral administration of BRB. The results suggest that BRBG is a potential agent for reducing glucose levels.Berberrubine （BRB） is the primary metabolite of berberine （BBR） that has shown a stronger glucose-lowering effect than BBR in vivo. On the other hand, BRB is quickly and extensively metabolized into berberrubine-9-O-β-D-glucuronide （BRBG） in rats after oral administration. In this study we compared the pharmacokinetic properties of BRB and BRBG in rats, and explored the mechanisms underlying their glucose-lowering activities. C57BL/6 mice with HFD-induced hyperglycemia were administered BRB （50 mg·kg^-1·d^-1, ig） for 6 weeks, which caused greater reduction in the plasma glucose levels than those caused by BBR （120 mg·kg^-1·d^-1） or BRB （25 mg·kg^-1·d^-1）. In addition, BRB dose-dependently decreased the activity of α-glucosidase in gut of the mice. After oral administration of BRB in rats, the exposures of BRBG in plasma at 3 different dosages （10, 40, 80 mg/kg） and in urine at different time intervals （0-4, 4-10, 10-24 h） were dramatically greater than those of BRB. In order to determine the effectiveness of BRBG in reducing glucose levels, we prepared BRBG from the urine pool of rats, and identified and confirmed it through LC-MS-IT-TOF and NMR spectra. In human normal liver cell line 1_-02 in vitro, treatment with BRB or BRBG （5, 20, 50 pmol/L） increased glucose consumption, enhanced glycogenesis, stimulated the uptake of the glucose analog 2-NBDG, and modulated the mRNA levels of glucose-6-phosphatase and hexokinase. However, both BBR and BRB improved 2-NBDG uptake in insulin-resistant L-02 cells, while BRBG has no effect. In conclusion, BRB exerts a stronger glucose-lowering effect than BBR in HFD-induced hyperglycemia mice. Although BRB significantly stimulated the insulin sensitivity and glycolysis in vitro, BRBG may have a greater contribution to the glucose-lowering effect because it has much greater system exposure than BRB after oral administration of BRB. The results suggest that BRBG is a potential agent for reducing glucose levels.

关 键 词：HYPERGLYCEMIA glucose-lowering effect BERBERINE berberrubine GLUCURONIDE （x-glycosidase HFD-induced hyperglycemiamodel of C57BL/6 mice human normal liver cell line 1_-02 PHARMACOKINETICS 

分 类 号：R[医药卫生]