| Chaperone proteins involved in troglitazone-induced toxicity in human hepatoma cell lines. | |
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MedLine Citation:
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PMID: 15525695 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Rawiwan Maniratanachote; Keiichi Minami; Miki Katoh; Miki Nakajima; Tsuyoshi Yokoi |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2004-11-03 |
Journal Detail:
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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:
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Created Date: 2005-01-05 Completed Date: 2005-05-05 Revised Date: 2010-09-17 |
Medline Journal Info:
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Nlm Unique ID: 9805461 Medline TA: Toxicol Sci Country: United States |
Other Details:
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Languages: eng Pagination: 293-302 Citation Subset: IM |
Affiliation:
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Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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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* Humans 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* Transfection |
| Chemical | |
Reg. No./Substance:
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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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