Direct toxicity of nonsteroidal antiinflammatory drugs for renal medullary cells

Abstract

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 Ϸ50% 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.acetaminophen ͉ aspirin ͉ salicylic acid ͉ indomethacin ͉ caffeine

Toxicity of Acetaminophen, Salicylic Acid, and Caffeine for First-Passage Rat Renal Inner Medullary Collecting Duct Cells

“…In contrast, adding SA to APAP and/or caffeine does not further reduce the cell number. The previous results with subconfluent mIMCD3 cells were qualitatively similar (Rocha et al, 2001). As little as 0.1 mM caffeine adds significantly to the effect of 0.5 mM SA plus 0.5 mM APAP (Fig.…”

“…When the p1rIMCD cells are confluent at 640 mOsmol/kg, 4 days of 2.0 mM SA or caffeine does not affect the cell number significantly (Fig. 3A), similar to the lack of effect of SA and caffeine, singly or combined, on confluent mIMCD3 cells (Rocha et al, 2001).…”

“…2A). A higher concentration of SA or APAP is required to reduce the number of subconfluent p1rIMCD cells than previously observed for subconfluent mIMCD3 cells (Rocha et al, 2001). SA or APAP (1.0 to 2.0 mM) reduces the subconfluent p1rIMCD cell number by approximately 50%, whereas only 0.5 mM is required to reduce the mIMCD3 cell number to the same extent.…”

“…3) from that on confluent mIMCD3 cells (Rocha et al, 2001) and that on subconfluent p1rIMCD cells (Fig. 2A).…”

“…The patients have progressive renal failure and are susceptible to the subsequent development of uroepithelial tumors. Combination of NSAIDs, often including caffeine, and chronic antidiuresis were implicated in the toxicity.In an effort to investigate this toxicity, we previously (Rocha et al, 2001) tested effects of salicylic acid (SA), acetaminophen (APAP), and caffeine on mouse renal inner medullary collecting duct (mIMCD3) cells (Rauchman et al, 1993). We found that when mIMCD3 cells are subconfluent, 0.5 mM SA or APAP reduces the number of viable cells by approximately 50%.…”