Direct toxicity of nonsteroidal antiinflammatory drugs for renal medullarycells

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 d rugs including aspirin (ASA), phenacetin. and caffeine. The mechanism of to xicity is unclear. We tested the effects of ASA, acetaminophen (APAF, the a ctive metabolite of phenacetin), caffeine, and other related drugs individu ally and in combination on mouse inner medullary collecting duct cells (mIM CD3). The number of rapidly proliferating cells was reduced by approximate to 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 e ffect of acetaminophen. pointing to a potential danger of the mixture. Cycl ooxygenase (COX) inhibitors, indomethacin and NS-398, did not reduce cell n umber except at concentrations greatly in excess of those that inhibit COX. Therefore, COX inhibition alone is not toxic, APAF arrests most cells in l ate G(1) and S and produces a mixed form of cell death with both oncosis (s wollen cells and nuclei) and apoptosis. APAF is known to inhibit the synthe sis of DNA and cause chromosomal aberrations due to inhibition of ribonucle otide reductase, Such effects of APAF might account for renal medullary cel l death in vivo and development of uroepithelial tumors from surviving cell s that have chromosomal aberrations.