Fluoroquinolones suppress gluconeogenesis by inhibiting fructose 1,6-bisphosphatase in primary monkey hepatocytes

被引:1
|
作者
Iguchi, Takuma [1 ]
Goto, Koichi [1 ]
Watanabe, Kyoko [2 ]
Hashimoto, Kazuyuki [2 ]
Suzuki, Takami [3 ]
Kishino, Hiroyuki [1 ]
Fujimoto, Kazunori [1 ]
Mori, Kazuhiko [1 ]
机构
[1] Daiichi Sankyo Co Ltd, Med Safety Res Labs, Edogawa Ku, 1-16-13 Kita Kasai, Tokyo 1348630, Japan
[2] Daiichi Sankyo Co Ltd, Biomarker & Translat Res Dept, Shinagawa Ku, 1-2-58 Hiromachi, Tokyo 1400005, Japan
[3] Daiichi Sankyo Co Ltd, Oncol Res Labs 1, Shinagawa Ku, 1-2-58 Hiromachi, Tokyo 1400005, Japan
关键词
Gluconeogenesis; Fructose 1,6-bisphosphatase; Fluoroquinolones; Hepatocyte; Cynomolgus monkey; PHOSPHOENOLPYRUVATE CARBOXYKINASE GENE; GLUCOSE-METABOLISM; INSULIN-SECRETION; GATIFLOXACIN; FRUCTOSE-1,6-BISPHOSPHATASE; LEVOFLOXACIN; DYSGLYCEMIA; EXPRESSION; HEALTH; MODEL;
D O I
10.1016/j.tiv.2020.104786
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
Dysglycemia is one of the most serious adverse events associated with the clinical use of certain fluoroquinolones. The purpose of this study was to investigate the effects of the representative fluoroquinolones moxifloxacin and gatifloxacin on hepatic gluconeogenesis using primary monkey hepatocytes. Glucose production was induced after the cells were incubated for 4 h with 10 mM sodium lactate and 1 mM sodium pyruvate as gluconeogenic substrates. Under these conditions, moxifloxacin and gatifloxacin dose-dependently suppressed gluconeogenesis at concentrations of 100 mu M or higher. Transcriptome analysis of rate-limiting enzymes involved in hepatic gluconeogenesis revealed that moxifloxacin and gatifloxacin at a concentration of 1000 mu M did not affect the expression of key gluconeogenic enzymes such as phosphoenolpyruvate carboxykinase, glucose 6-phosphatase, and fructose 1,6-bisphosphatase. Furthermore, metabolome analysis, in vitro glucose production assay using additional gluconeogenic substrates, and fructose 1,6-bisphosphatase assay using the cell extracts showed that fluoroquinolones enzymatically suppressed hepatic gluconeogenesis by inhibiting fructose 1,6-bisphosphatase. These inhibitory effects may involve in the clinically relevant dysglycemia associated with fluoroquinolones in human.
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页数:7
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