Feasibility of the functional expression of the human organic anion transporting polypeptide 1B1 (OATP1B1) and its genetic variant 521T/C in the mouse liver.
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.
CKD Research Institute, 315-20 Dongbaekjukjeon-daero, Giheung-gu, Yongin-si, Gyeonggi-do 446-916, South Korea.
Yoon-Jee
YJ
Chae
Daewoong Life Science Research Institute, 72 Dugye-ro, Pogok-eup, Cheoin-gu, Yongin-si, Gyeonggi-do 449-814, South Korea.
Kyeong-Ryoon
KR
Lee
Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon 305-343, South Korea.
Jong-Hwa
JH
Lee
Department of Pharmaceutics, College of Pharmacy, Seoul National University, Gwanak 599, Gwanak-ro, Gwanak-gu, Seoul 151-742, South Korea.
Wooin
W
Lee
Department of Pharmaceutics, College of Pharmacy, Seoul National University, Gwanak 599, Gwanak-ro, Gwanak-gu, Seoul 151-742, South Korea.
Dae-Duk
DD
Kim
Department of Pharmaceutics, College of Pharmacy, Seoul National University, Gwanak 599, Gwanak-ro, Gwanak-gu, Seoul 151-742, South Korea. Electronic address: sukjae@snu.ac.kr.
Suk-Jae
SJ
Chung
College of Pharmacy, Gachon University, 191 Hambakmoei-ro, Yeonsu-gu, Incheon 406-799, South Korea. Electronic address: hjmaeng@gachon.ac.kr.
Han-Joo
HJ
Maeng
D000818:Animals; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D014644:Genetic Variation; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism*; D027381:Liver-Specific Organic Anion Transporter 1 / Q000235:genetics* / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics; D008297:Male; D008813:Mice, Inbred ICR; D017035:Pravastatin / Q000097:blood / Q000493:pharmacokinetics
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; C503999:SLCO1B1 protein, human; D008156:Luciferases; D017035:Pravastatin
521T>C; Hydrodynamic gene delivery; In vivo animal model; Liver uptake; Pharmacokinetics; Pravastatin; hOATP1B1