PROTEIN ARYLATION PRECEDES ACETAMINOPHEN TOXICITY IN A DYNAMIC ORGAN SLICE CULTURE OF MOUSE KIDNEY

Acetaminophen (APAP) is an analgesic and antipyretic agent which may c ause hepatotoxicity and nephrotoxicity with overdose in man and labora tory animals. In vivo studies suggest that in situ activation of APAP contributes to the development of nephrotoxicity. Associated with targ et organ toxicity is selective arylation of proteins, with a 58-kDa ac etaminophen binding protein (58-ABP) being the most prominent cytosoli c target. In this study a mouse kidney slice model was developed to fu rther evaluate the contribution of in situ activation of APAP to the d evelopment of nephrotoxicity and to determine the selectivity of prote in arylation. Precision cut kidney slices from male CD-1 mice were inc ubated with selected concentrations of APAP (0-25 mM) for 2 to 24 hr. APAP caused a dose- and time-dependent decrease in nonprotein sulfhydr yls (NPSH), ATP content, and K+ retention. Preceding toxicity was aryl ation of cytosolic proteins, the most prominent one being the 58-ABP. The association of 58-ABP arylation with APAP toxicity in this mouse k idney slice model is consistent with earlier, in vivo results and demo nstrates the importance of in situ activation of APAP for the developm ent of nephrotoxicity. Precision cut renal slices and dynamic organ cu lture are a good model for further mechanistic studies of APAP-induced renal toxicity. (C) 1996 Society of Toxicology.