Document Detail

Chaperone proteins involved in troglitazone-induced toxicity in human hepatoma cell lines.
MedLine Citation:
PMID:  15525695     Owner:  NLM     Status:  MEDLINE    
Troglitazone (TRO), an effective thiazolidinedione antidiabetic agent, was reported to produce idiosyncratic hepatotoxic effects in some individuals. In contrast, rosiglitazone (RSG), in the same group of agents, has no significant toxic effects and now is widely used. In this study, human hepatoma (HepG2) cell lines were exposed to various doses of TRO as well as RSG (0, 25, 50, and 75 microM) for 48 h. Cell lysates were separated by two-dimensional electrophoresis, and the gels were stained with coomassie brilliant blue to compare the spot profiles. The greatest protein expression at a MW of 75 kDa and isoelectric point of 5 was specifically increased with TRO treatments of 50 and 75 microM. The spot was identified as a mixture of immunoglobulin heavy chain binding protein (BiP) and, to a lesser extent, protein disulfide isomerase-related protein (PDIrp). Immunoblot analyses showed that the BiP protein was dose-dependently increased by TRO treatment and, to a lower degree, by RSG. These effects were also correlated with the high induction of BiP mRNA by TRO (50 and 75 microM) and the lower induction by RSG. However, both treatments showed no significant effects on PDIrp expression. The toxic effects of TRO in relation to the overexpression of BiP were also demonstrated in HLE cells, another human hepatoma cell line. In HLE cells, the inhibition of BiP expression by small interference RNA rendered cells more susceptible to the toxic effects of TRO. These results suggest that the overexpression of BiP is a defense mechanism of the endoplasmic reticulum in response to TRO-induced toxicity.
Rawiwan Maniratanachote; Keiichi Minami; Miki Katoh; Miki Nakajima; Tsuyoshi Yokoi
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2004-11-03
Journal Detail:
Title:  Toxicological sciences : an official journal of the Society of Toxicology     Volume:  83     ISSN:  1096-6080     ISO Abbreviation:  Toxicol. Sci.     Publication Date:  2005 Feb 
Date Detail:
Created Date:  2005-01-05     Completed Date:  2005-05-05     Revised Date:  2010-09-17    
Medline Journal Info:
Nlm Unique ID:  9805461     Medline TA:  Toxicol Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  293-302     Citation Subset:  IM    
Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
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MeSH Terms
Amino Acid Sequence
Carcinoma, Hepatocellular / drug therapy,  metabolism*,  pathology
Cell Line, Tumor / drug effects
Cell Survival / drug effects
Chromans / toxicity*
Dose-Response Relationship, Drug
Gene Expression Regulation / drug effects
Heat-Shock Proteins / antagonists & inhibitors,  genetics,  metabolism*
Hypoglycemic Agents / toxicity*
Liver Neoplasms / drug therapy,  metabolism*,  pathology
Molecular Chaperones / antagonists & inhibitors,  genetics,  metabolism*
Molecular Sequence Data
Proteins / genetics,  metabolism*
RNA Interference
RNA, Messenger / metabolism
RNA, Small Interfering / biosynthesis,  genetics,  pharmacology
Reverse Transcriptase Polymerase Chain Reaction
Thiazolidinediones / toxicity*
Reg. No./Substance:
0/Chromans; 0/Heat-Shock Proteins; 0/Hypoglycemic Agents; 0/Molecular Chaperones; 0/PDIR protein, human; 0/Proteins; 0/RNA, Messenger; 0/RNA, Small Interfering; 0/Thiazolidinediones; 0/molecular chaperone GRP78; 122320-73-4/rosiglitazone; 97322-87-7/troglitazone

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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