| Direct toxicity of nonsteroidal antiinflammatory drugs for renal medullary cells. | |
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MedLine Citation:
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PMID: 11320259 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Antipyretic analgesics, taken in large doses over a prolonged period, cause a specific form of kidney disease, characterized by papillary necrosis and interstitial scarring. Epidemiological evidence incriminated mixtures of drugs including aspirin (ASA), phenacetin, and caffeine. The mechanism of toxicity is unclear. We tested the effects of ASA, acetaminophen (APAF, the active metabolite of phenacetin), caffeine, and other related drugs individually and in combination on mouse inner medullary collecting duct cells (mIMCD3). The number of rapidly proliferating cells was reduced by approximately 50% by 0.5 mM ASA, salicylic acid, or APAF. The drugs had less effect on confluent cells, which proliferate slowly. Thus, the slow in vivo turnover of IMCD cells could explain why clinical toxicity requires very high doses of these drugs over a very long period. Caffeine greatly potentiated the effect of acetaminophen, pointing to a potential danger of the mixture. Cyclooxygenase (COX) inhibitors, indomethacin and NS-398, did not reduce cell number except at concentrations greatly in excess of those that inhibit COX. Therefore, COX inhibition alone is not toxic. APAF arrests most cells in late G(1) and S and produces a mixed form of cell death with both oncosis (swollen cells and nuclei) and apoptosis. APAF is known to inhibit the synthesis of DNA and cause chromosomal aberrations due to inhibition of ribonucleotide reductase. Such effects of APAF might account for renal medullary cell death in vivo and development of uroepithelial tumors from surviving cells that have chromosomal aberrations. |
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Authors:
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G M Rocha; L F Michea; E M Peters; M Kirby; Y Xu; D R Ferguson; M B Burg |
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Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 98 ISSN: 0027-8424 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2001 Apr |
Date Detail:
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Created Date: 2001-04-26 Completed Date: 2001-05-21 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 5317-22 Citation Subset: IM |
Affiliation:
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Laboratory of Kidney and Electrolytes Metabolism, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Acetaminophen
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toxicity Animals Anti-Inflammatory Agents, Non-Steroidal / toxicity* Apoptosis / drug effects* Aspirin / toxicity Caffeine / toxicity Cell Division / drug effects Cell Line Cyclooxygenase Inhibitors / toxicity Drug Interactions Flow Cytometry Indomethacin / toxicity Kidney Tubules, Collecting / cytology*, drug effects*, ultrastructure Mice Microscopy, Electron Salicylic Acid / toxicity |
| Chemical | |
Reg. No./Substance:
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0/Anti-Inflammatory Agents, Non-Steroidal; 0/Cyclooxygenase Inhibitors; 103-90-2/Acetaminophen; 50-78-2/Aspirin; 53-86-1/Indomethacin; 58-08-2/Caffeine; 69-72-7/Salicylic Acid |
| Comments/Corrections | |
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