Species-specific toxicity of troglitazone on rats and human by gel entrapped hepatocytes |
| |
Authors: | Shen Chong Meng Qin Zhang Guoliang |
| |
Institution: | a College of Materials Science and Chemical Engineering, Zhejiang University, Zhejiang 310027, PR Chinab Institute of Biological and Environmental Engineering, Zhejiang University of Technology, Zhejiang 310012, China |
| |
Abstract: | Troglitazone, despite passing preclinical trials on animals, was shortly withdrawn from market due to its severe hepatotoxicity in clinic. As rat hepatocyte monolayer consistently showed sensitive troglitazone toxicity as human hepatocyte monolayer in contrast to the species-specific toxicity in vivo, this paper utilized both hepatocytes in three-dimensional culture of gel entrapment to reflect the species difference on hepatotoxicity. Rat hepatocytes in gel entrapment did not show obvious cellular damage even under a long-term exposure for 21 days while gel entrapped human hepatocytes significantly displayed oxidative stress, steatosis, mitochondrial damage and cell death at a short exposure for 4 days. As a result, the detected species-specific toxicity of troglitazone between gel entrapped rat and human hepatocytes consisted well with the situation in vivo but was in a sharp contrast to the performance of two hepatocytes by monolayer culture. Such contradictory toxicity of rat hepatocytes between monolayer and gel entrapment culture could be explained by the fact that troglitazone was cleared more rapidly in gel entrapment than in monolayer culture. Similarly, the differential clearance of troglitazone in rat and human might also explain its species-specific toxicity. Therefore, gel entrapment of hepatocytes might serve as a platform for evaluation of drug toxicity at early stage of drug development by reducing costs, increasing the likelihood of clinical success and limiting human exposure to unsafe drugs. |
| |
Keywords: | 3D three-dimensional AUC area under the plasma concentration-time curve Cmax peak concentration in plasma CL apparent oral clearance DTNB 5 5-dithiobis(2-nitrobenzoic acid) EC50 half maximal effective concentration FDA Food and Drug Administration GSH glutathione MDA malondialdehyde MTT methyl thiazolyl tetrazolium HBV hepatitis virus B HCV hepatitis virus C HIV human immunodeficiency virus LDH lactate dehydrogenase PBS phosphate buffered saline TBA thiobarbituric acid t1/2 half-life TBARS thiobarbituric acid reactive substances |
本文献已被 ScienceDirect PubMed 等数据库收录! |
|