title: Micropatterned coculture of hepatocytes on electrospun fibers as a potential in vitro model for predictive drug metabolism.
abstract: The liver is the major organ of importance to determine drug dispositions in the body, thus the development of hepatocyte culture systems is of great scientific and practical interests to provide reliable and predictable models for in vitro drug screening. In the current study, to address the challenges of a rapid function loss of primary hepatocytes, the coculture of hepatocytes with fibroblasts and endothelial cells (Hep-Fib-EC) was established on micropatterned fibrous scaffolds. Liver-specific functions, such as the albumin secretion and urea synthesis, were well maintained in the coculture system, accompanied by a rapid formation of multicellular hepatocyte spheroids. The activities of phase I (CYP3A11 and CYP2C9) and phase II enzymes indicated a gradual increase for cocultured hepatocytes, and a maximum level was achieved after 5 days and maintained throughout 15 days of culture. The metabolism testing on model drugs indicated that the scaled clearance rates for hepatocytes in the Hep-Fib-EC coculture system were significantly higher than those of other culture methods, and a linear regression analysis indicated good correlations between the observed data of rats and in vitro predicted values during 15 days of culture. In addition, the enzyme activities and drug clearance rates of hepatocytes in the Hep-Fib-EC coculture model experienced sensitive responsiveness to the inducers and inhibitors of metabolizing enzymes. These results demonstrated the feasibility of micropatterned coculture of hepatocytes as a potential in vitro testing model for the prediction of in vivo drug metabolism.
authors.affiliation: Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China; College of Food Science, Sichuan Agricultural University, Yaan 625014, PR China.
authors.forename: Yaowen
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China.
authors.forename: Jiaojun
authors.initials: J
authors.lastname: Wei
authors.affiliation: Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China.
authors.forename: Jinfu
authors.initials: J
authors.lastname: Lu
authors.affiliation: Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Lei
authors.affiliation: Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China.
authors.forename: Shili
authors.initials: S
authors.lastname: Yan
authors.affiliation: Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China. Electronic address: xhli@swjtu.edu.cn.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D008297:Male; D018613:Microscopy, Confocal; D008855:Microscopy, Electron, Scanning; D008874:Midazolam / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D014044:Tolbutamide / Q000378:metabolism; D014859:Warfarin / Q000378:metabolism
chemical_list: D004364:Pharmaceutical Preparations; D014859:Warfarin; D014044:Tolbutamide; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam
keywords: Drug metabolism; Drug-drug interaction; Hepatocyte coculture; Hepatocyte spheroid; Micropatterned fibrous mats