{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T15:24:30Z","timestamp":1781105070256,"version":"3.54.1"},"reference-count":28,"publisher":"National Academy of Sciences","issue":"9","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2001,4,24]]},"abstract":"<jats:p>\n                    Antipyretic analgesics, taken in large doses over a prolonged\n period, cause a specific form of kidney disease, characterized by\n papillary necrosis and interstitial scarring. Epidemiological evidence\n incriminated mixtures of drugs including aspirin (ASA), phenacetin, and\n caffeine. The mechanism of toxicity is unclear. We tested the effects\n of ASA, acetaminophen (APAF, the active metabolite of phenacetin),\n caffeine, and other related drugs individually and in combination on\n mouse inner medullary collecting duct cells (mIMCD3). The number of\n rapidly proliferating cells was reduced by \u224850% by 0.5 mM ASA,\n salicylic acid, or APAF. The drugs had less effect on confluent cells,\n which proliferate slowly. Thus, the slow\n                    <jats:italic>in vivo<\/jats:italic>\n                    turnover of IMCD cells could explain why clinical toxicity requires\n very high doses of these drugs over a very long period. Caffeine\n greatly potentiated the effect of acetaminophen, pointing to a\n potential danger of the mixture. Cyclooxygenase (COX) inhibitors,\n indomethacin and NS-398, did not reduce cell number except at\n concentrations greatly in excess of those that inhibit COX. Therefore,\n COX inhibition alone is not toxic. APAF arrests most cells in late\n G\n                    <jats:sub>1<\/jats:sub>\n                    and S and produces a mixed form of cell death with both\n oncosis (swollen cells and nuclei) and apoptosis. APAF is known\n to inhibit the synthesis of DNA and cause chromosomal aberrations due\n to inhibition of ribonucleotide reductase. Such effects of APAF might\n account for renal medullary cell death\n                    <jats:italic>in vivo<\/jats:italic>\n                    and\n development of uroepithelial tumors from surviving cells that have\n chromosomal aberrations.\n                  <\/jats:p>","DOI":"10.1073\/pnas.091057698","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:44:19Z","timestamp":1027680259000},"page":"5317-5322","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":39,"title":["Direct toxicity of nonsteroidal antiinflammatory drugs for renal medullary cells"],"prefix":"10.1073","volume":"98","author":[{"given":"Gerson M.","family":"Rocha","sequence":"first","affiliation":[{"name":"Laboratory of Kidney and Electrolytes Metabolism,\r Hematology Branch, and Microscope Core\r Facility, National Heart, Lung, and Blood Institute, Bethesda, MD\r 20892; and Department of Pharmacology, University of\r Cambridge, Cambridge CB2 1QJ, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis F.","family":"Michea","sequence":"additional","affiliation":[{"name":"Laboratory of Kidney and Electrolytes Metabolism,\r Hematology Branch, and Microscope Core\r Facility, National Heart, Lung, and Blood Institute, Bethesda, MD\r 20892; and Department of Pharmacology, University of\r Cambridge, Cambridge CB2 1QJ, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenia M.","family":"Peters","sequence":"additional","affiliation":[{"name":"Laboratory of Kidney and Electrolytes Metabolism,\r Hematology Branch, and Microscope Core\r Facility, National Heart, Lung, and Blood Institute, Bethesda, MD\r 20892; and Department of Pharmacology, University of\r Cambridge, Cambridge CB2 1QJ, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha","family":"Kirby","sequence":"additional","affiliation":[{"name":"Laboratory of Kidney and Electrolytes Metabolism,\r Hematology Branch, and Microscope Core\r Facility, National Heart, Lung, and Blood Institute, Bethesda, MD\r 20892; and Department of Pharmacology, University of\r Cambridge, Cambridge CB2 1QJ, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhui","family":"Xu","sequence":"additional","affiliation":[{"name":"Laboratory of Kidney and Electrolytes Metabolism,\r Hematology Branch, and Microscope Core\r Facility, National Heart, Lung, and Blood Institute, Bethesda, MD\r 20892; and Department of Pharmacology, University of\r Cambridge, Cambridge CB2 1QJ, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas R.","family":"Ferguson","sequence":"additional","affiliation":[{"name":"Laboratory of Kidney and Electrolytes Metabolism,\r Hematology Branch, and Microscope Core\r Facility, National Heart, Lung, and Blood Institute, Bethesda, MD\r 20892; and Department of Pharmacology, University 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