title: Involvement of pregnane X receptor in the suppression of carboxylesterases by metformin in vivo and in vitro, mediated by the activation of AMPK and JNK signaling pathway.
abstract: Type 2 diabetes mellitus (T2D) is a complex metabolic disorder requiring polypharmacy treatment in clinic, with metformin being widely used antihyperglycemic drug. However, the mechanisms of metformin as a perpetrator inducing potential drug-drug interactions and adverse drug reactions are scarcely known to date. Carboxylesterases (CESs) are major hydrolytic enzymes highly expressed in the liver, including mouse carboxylesterase 1d (Ces1d) and Ces1e. In the present study, experiments are designed to investigate the effects and mechanisms of metformin on Ces1d and Ces1e in vivo and in vitro. In results, metformin suppresses the expression and activity of Ces1d and Ces1e in a dose- and time-dependent manner. The decreased expression of nuclear receptor PXR and its target gene P-gp indicates the involvements of PXR in the suppressed expression of carboxylesterases by metformin. Furthermore, metformin significantly suppresses the phosphorylation of AMPK and JNK, and the suppression of carboxylesterases induced by metformin is repeatedly abolished by AMPK inhibitor Compound C and JNK inhibitor SP600125. It implies that the activation of AMPK and JNK pathways mediates the suppression of carboxylesterases by metformin. The findings deserve further elucidation including clinical trials and have a potential to make contribution for the rational medication in the treatment of T2D patients.
authors.affiliation: Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Enfang
authors.initials: E
authors.lastname: Shan
authors.affiliation: Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Shuangcheng
authors.initials: S
authors.lastname: He
authors.affiliation: Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Dongbao
authors.initials: D
authors.lastname: Chu
authors.affiliation: Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Dinghao
authors.initials: D
authors.lastname: Ge
authors.affiliation: Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Yunran
authors.initials: Y
authors.lastname: Zhan
authors.affiliation: Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China. Electronic address: jianyang@njmu.edu.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China. Electronic address: xiong.jing@njmu.edu.cn.
authors.forename: Jing
authors.initials: J
authors.lastname: Xiong
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002478:Cells, Cultured; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D008813:Mice, Inbred ICR; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000378:metabolism
chemical_list: D007004:Hypoglycemic Agents; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D008687:Metformin; D055372:AMP-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D002265:Carboxylic Ester Hydrolases; C545375:carboxylesterase 1, mouse
keywords: AMP-activated protein kinase; Carboxylesterases; Clopidogrel bisulfate (PubChem CID: 115366); Compound C (PubChem CID: 1e1524144); Irinotecan hydrochloride (PubChem CID: 74990); Metformin (PubChem CID: 4091); P-glycoprotein; Para-nitrophenylacetate (PubChem CID: 6931101); Pregnane X receptor; Rhodamine 123 (PubChem CID: 65217); SP600125 (PubChem CID: 8515); Type 2 diabetes; c-Jun N-terminal kinase