title: Acetaminophen-induced hepatotoxicity of gel entrapped rat hepatocytes in hollow fibers.
abstract: An important application of primary hepatocyte cultures is for hepatotoxicity research. In this paper, gel entrapment culture of rat hepatocytes in miniaturized BAL system were evaluated as a potential in vitro model for hepatotoxicity studies in comparison to monolayer cultures. After exposure for 24 and 48 h to acetaminophen (2.5 mM), gel entrapped hepatocytes were more severely damaged than hepatocyte monolayer detected by methyl thiazolyl tetrazolium (MTT) reduction, intracellular glutathione (GSH) content, reactive oxygen species (ROS) levels, urea genesis and albumin synthesis. CYP 2E1 activities detected by 4-nitrocatechol (4-NC) formation were higher in gel entrapped hepatocytes than in hepatocyte monolayers while the addition of CYP 2E1 inhibitor, diethyl-dithiocarbamate (DDC), more significantly reduced acetaminophen-induced toxicity in gel entrapped hepatocytes. In addition, protective effects of GSH, liquorice extract and glycyrrhizic acid against acetaminophen hepatotoxicity were clearly observed in gel entrapped hepatocytes but not in hepatocyte monolayer at an incubation time of 48 h. Overall, gel entrapped hepatocytes showed higher sensitivities to acetaminophen-induced hepatotoxicity than hepatocyte monolayer by a mechanism that higher CYP 2E1 activities of gel entrapped hepatocytes could induce more severe acetaminophen toxicity. This indicates that gel entrapped hepatocytes in hollow fiber system could be a promising model for toxicological study in vitro.
authors.affiliation: College of Materials Science and Chemical Engineering, Zhejiang University, Zhejiang 310027, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Shen
authors.affiliation: College of Materials Science and Chemical Engineering, Zhejiang University, Zhejiang 310027, China; Institute of Biological and Environmental Engineering, Zhejiang University of Technology, Zhejiang 310032, China.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Zhang
authors.affiliation: College of Materials Science and Chemical Engineering, Zhejiang University, Zhejiang 310027, China.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Qiu
authors.affiliation: College of Materials Science and Chemical Engineering, Zhejiang University, Zhejiang 310027, China. Electronic address: mengq@zju.edu.cn.
authors.forename: Qin
authors.initials: Q
authors.lastname: Meng
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D002396:Catechols / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D005782:Gels / Q000737:chemistry / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D002396:Catechols; D005782:Gels; D017382:Reactive Oxygen Species; D000082:Acetaminophen; D019392:Cytochrome P-450 CYP2E1; D005978:Glutathione; C001833:4-nitrocatechol