Feasibility of the functional expression of the human organic anion transporting polypeptide 1B1 (OATP1B1) and its genetic variant 521T/C in the mouse liver

详细信息    查看全文

• 作者：Yoon-Jee Chae^a ; Kyeong-Ryoon Lee^b ; Jong-Hwa Lee^c ; Wooin Lee^d ; Dae-Duk Kim^d ; Suk-Jae Chung^d ; ^{sukjae@snu.ac.kr} ; Han-Joo Maeng^e ; ^{hjmaeng@gachon.ac.kr}
• 关键词：ALP ; alkaline phosphatase ; ALT ; alanine aminotransferase ; AST ; aspartate aminotransferase ; AUC ; the area under the plasma concentration-time curve ; CLapp ; hep ; hepatic uptake clearance ; hOATP1B1 ; human organic anion transporting polypeptide 1B1 ; HGD ; hydrodynamic gene delivery ; HMG-CoA ; 3-hydroxy-3-methylglutaryl ; IS ; internal standard ; LC-MS ; liquid chromatography-mass spectrometry ; mOATPs ; mouse organic anion transporting polypeptides ; RT-PCR ; reverse transcription-polymerase chain reaction ; S
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2017
• 出版时间：1 January 2017
• 年：2017
• 卷：96
• 期：Complete
• 页码：28-36
• 全文大小：953 K
• 卷排序：96

文摘

The objective of this study was to examine the feasibility of functional expression of the human organic anion transporting polypeptide 1B1 (hOATP1B1) forms in the liver of the mouse. After the mouse received the gene of interest (i.e., luciferase as the reporter or hOATP1B1) via hydrodynamic gene delivery (HGD) method, the expression was found to be liver-specific while alterations in the serum biochemistry and hepatocyte histology were apparently transient and reversible. The reporter activity was also detected in the plasma, but not in the blood cell in mice that received HGD, suggesting that the protein is probably released due to transiently increased permeability in hepatocytes by HGD. Using this delivery condition, the expression of hOATP1B1 was readily detected in the liver, but not in other tissues, of the mice receiving HGD for the transporter gene. Compared with the sham control mice, the uptake of pravastatin into the liver increased significantly in mice receiving hOATP1B1 wild type; the uptake parameters decreased consistently in mice expressing the 521T>C variant compared with that of the wild type control. These observations suggest that the functional expression of human transporter gene in mice is feasible, further suggesting that this treatment is practically useful in the pharmacokinetic studies for hOATP1B1 substrates.