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PNAS | April 24, 2001 | vol. 98 | no. 9 | 5317-5322
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Pharmacology
 Direct toxicity of nonsteroidal antiinflammatory drugs for renal medullary cells

(acetaminophen / aspirin / salicylic acid / indomethacin / caffeine)

Gerson M. Rocha*,dagger , Luis F. Michea*,dagger , Eugenia M. Peters*, Martha KirbyDagger , Yuhui Xu§, Douglas R. Ferguson*,, and Maurice B. Burg*,||

* Laboratory of Kidney and Electrolytes Metabolism, Dagger  Hematology Branch, and § Microscope Core Facility, National Heart, Lung, and Blood Institute, Bethesda, MD 20892; and  Department of Pharmacology, University of Cambridge, Cambridge CB2 1QJ, United Kingdom

Contributed by Maurice B. Burg, February 5, 2001

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 approx 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 G1 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.

dagger G.M.R. and L.F.M. contributed equally to this work.

|| To whom reprint requests should be addressed at: Building 10, Room 6N260, National Institutes of Health, Bethesda, MD 20892-1603. E-mail: maurice-burg{at}nih.gov.

www.pnas.org/cgi/doi/10.1073/pnas.091057698
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