| The mechanism of acute cytotoxicity of triethylphosphine gold(I) complexes. I. Characterization of triethylphosphine gold chloride-induced biochemical and morphological changes in isolated hepatocytes. | |
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MedLine Citation:
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PMID: 3660408 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Triethylphosphine gold complexes are effective therapeutic agents used for the treatment of rheumatoid arthritis. Many of those molecules are also highly cytotoxic in vitro and can inhibit DNA and protein synthesis. Preliminary experiments have indicated that triethylphosphine gold chloride (TEPAu) may induce the peroxidative decomposition of cellular membrane lipids. The purpose of these investigations therefore was to evaluate the role of lipid peroxidation in the mechanism of acute cytotoxicity of a gold(I) coordination complex, TEPAu, and to examine the early morphological and biochemical changes induced by TEPAu in suspensions of freshly isolated rat hepatocytes. TEPAu caused a rapid loss of cell viability at concentrations above 25 microM which was significantly different from that of control by 60 min and complete by 180 min of incubation. TEPAu also depleted cells of reduced glutathione (GSH) and increased the formation of malondialdehyde (MDA) by 60 min. Incubation of cells with either of the antioxidants, N,N'-diphenyl-p-phenylenediamine (DPPD) or promethazine blocked the formation of MDA but did not alter the time course of cell death or GSH depletion induced by TEPAu. TEPAu also caused a decrease in cellular NADPH and NADH by 10 min. Electron microscopy of hepatocytes exposed to TEPAu revealed early (5 min) formation of flocculent electron-dense precipitates within condensed mitochondria. These changes characteristically preceded cell death. Energy-dispersive electron-probe microanalysis indicated that the electron-dense precipitates did not contain detectable amounts of gold. TEPAu also caused a concentration-dependent decrease in cellular ATP and oxygen consumption in isolated rat hepatocytes. These data suggest that lipid peroxidation, as indicated by the formation of MDA, is probably not a major mechanism by which triethylphosphine gold complexes lethally injure cells. These data, therefore, suggest that mitochondria may be target organelles in TEPAu-induced toxicity to isolated rat hepatocytes. |
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Authors:
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G F Rush; P F Smith; D W Alberts; C K Mirabelli; R M Snyder; S T Crooke; J Sowinski; H B Jones; P J Bugelski |
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Publication Detail:
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Type: In Vitro; Journal Article |
Journal Detail:
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Title: Toxicology and applied pharmacology Volume: 90 ISSN: 0041-008X ISO Abbreviation: Toxicol. Appl. Pharmacol. Publication Date: 1987 Sep |
Date Detail:
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Created Date: 1987-11-12 Completed Date: 1987-11-12 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 0416575 Medline TA: Toxicol Appl Pharmacol Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 377-90 Citation Subset: IM |
Affiliation:
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Department of Investigative Toxicology, Smith Kline and French Laboratories, Philadelphia, Pennsylvania 19101. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Anti-Inflammatory Agents, Non-Steroidal / toxicity* Cell Survival / drug effects Dose-Response Relationship, Drug Glutathione / analysis L-Lactate Dehydrogenase / secretion Lipid Peroxides / metabolism Liver / analysis, drug effects*, pathology Male Malondialdehyde / metabolism Mitochondria, Liver / drug effects NADP / metabolism Organogold Compounds Organometallic Compounds / toxicity* Organophosphorus Compounds / toxicity* Oxygen Consumption / drug effects Phenylenediamines / pharmacology Phosphines* Rats Rats, Inbred Strains |
| Chemical | |
Reg. No./Substance:
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0/Anti-Inflammatory Agents, Non-Steroidal; 0/Lipid Peroxides; 0/Organogold Compounds; 0/Organometallic Compounds; 0/Organophosphorus Compounds; 0/Phenylenediamines; 0/Phosphines; 15529-90-5/triethyl phosphine gold; 53-59-8/NADP; 542-78-9/Malondialdehyde; 70-18-8/Glutathione; 74-31-7/N,N'-diphenyl-4-phenylenediamine; EC 1.1.1.27/L-Lactate Dehydrogenase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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