title: In vitro assessment of the glucose-lowering effects of berberrubine-9-O-β-D-glucuronide, an active metabolite of berberrubine.
abstract: 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 L-O2 in vitro, treatment with BRB or BRBG (5, 20, 50 μmol/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-O2 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.
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Na
authors.initials: N
authors.lastname: Yang
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Run-Bin
authors.initials: RB
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
authors.forename: Xing-Long
authors.initials: XL
authors.lastname: Chen
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Le
authors.initials: L
authors.lastname: Zhen
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Ge
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Yu-Qing
authors.initials: YQ
authors.lastname: Zhao
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Jun
authors.initials: J
authors.lastname: He
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Jian-Liang
authors.initials: JL
authors.lastname: Geng
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Jia-Hua
authors.initials: JH
authors.lastname: Guo
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Yu
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Fei
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Si-Qi
authors.initials: SQ
authors.lastname: Feng
authors.affiliation: Department of Pharmacology, Clinical Research Institute of Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing 210009, China.
authors.forename: Xuan-Xuan
authors.initials: XX
authors.lastname: Zhu
authors.affiliation: Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Pharmacy School at Yantai University, Yantai 264005, China.
authors.forename: Hong-Bo
authors.initials: HB
authors.lastname: Wang
authors.affiliation: Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Pharmacy School at Yantai University, Yantai 264005, China.
authors.forename: Feng-Hua
authors.initials: FH
authors.lastname: Fu
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Ji-Ye
authors.initials: JY
authors.lastname: Aa
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Guang-Ji
authors.initials: GJ
authors.lastname: Wang
mesh_terms: D000818:Animals; D001599:Berberine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000652:urine; D020719:Glucuronides / Q000097:blood / Q000627:therapeutic use* / Q000652:urine; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy*; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008810:Mice, Inbred C57BL; D017207:Rats, Sprague-Dawley
chemical_list: D020719:Glucuronides; D007004:Hypoglycemic Agents; C000615774:berberrubine-9-O-glucuronide; D001599:Berberine; C115958:berberrubine