COMPARATIVE CYTOTOXICITY OF 5-AMINOSALICYLIC ACID (MESALAZINE) AND RELATED-COMPOUNDS IN DIFFERENT CELL-LINES

Nonsteroidal anti-inflammatory drugs can cause serious side-effects su ch as tubulo-interstitial nephritis. Mesalazine (5-ASA, 5-aminosalicyl ic acid) is used for the treatment of colitis ulcerosa, Crohn disease, and other diseases; it has been found to induce necrosis of both prox imal convoluted tubules and renal papillaries. The comparative cytotox icity of 3-, 4-, and 5-aminosalicylic acid, acetylsalicylic acid (AcSA ), and the parent compound salicylic acid (SA) was investigated for th e free acids and for their sodium salts. The interaction with endogeno us glutathione (GSH) was also investigated. Four established cell line s were used: MDCK, LLC-PK1, NRK as renal cells, and HepG2 as hepatic c ells. The free acid compounds were less toxic than their corresponding salts. Acidic 5-ASA was the most toxic of the three isomers in MDCK a nd LLC-PK1 cells, while NRK and HepG2 were more susceptible to acidic 3-ASA. Addition of NaOH modified the relative toxicity of 3-ASA and 5- ASA. The LLC-PK1 and HepG2 cells were more sensitive to the test chemi cals as their salts than were the NRK and MDCK cells. SA and 5-ASA dec reased the GSH content in renal cells and increased it in HepG2. GSH d epletion with L-buthionine-(S,R)-sulfoximine enhanced the toxicity onl y for SA in NRK and for 5-ASA and AcSA in HepG2. No correlation betwee n endogenous GSH and the susceptibility of MDCK and LLC-PK1 to the tes t compounds was observed. The results suggest that no typical nephroto xic effect occurred. No explanation could be found for the tubulo-inte rstitial nephritis caused by 5-ASA therapy.