Protein arylation precedes acetaminophen toxicity in a dynamic organ slice culture of mouse kidney

Debie J. Hoivik, Robyn L. Fisher, Klaus Brendel, A Jay Gandolfi, Edward A. Khairallah, Steven D. Cohen

Research output: Contribution to journalArticle

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Abstract

Acetaminophen (APAP) is an analgesic and antipyretic agent which may cause hepatotoxicity and nephrotoxicity with overdose in man and laboratory animals. In vivo studies suggest that in situ activation of APAP contributes to the development of nephrotoxicity. Associated with target organ toxicity is selective arylation of proteins, with a 58-kDa acetaminophen binding protein (58-ABP) being the most prominent cytosolic target. In this study a mouse kidney slice model was developed to further evaluate the contribution of in situ activation of APAP to the development of nephrotoxicity and to determine the selectivity of protein arylation. Precision cut kidney slices from male CD-1 mice were incubated with selected concentrations of APAP (0-25 mM) for 2 to 24 hr. APAP caused a dose- and time-dependent decrease in nonprotein sulfhydryls (NPSH), ATP content, and K+ retention. Preceding toxicity was arylation of cytosolic proteins, the most prominent one being the 58-ABP. The association of 58-ABP arylation with APAP toxicity in this mouse kidney slice model is consistent with earlier, in vivo results and demonstrates the importance of in situ activation of APAP for the development of nephrotoxicity. Precision cut renal slices and dynamic organ culture are a good model for further mechanistic studies of APAP-induced renal toxicity.

Original languageEnglish (US)
Pages (from-to)99-104
Number of pages6
JournalToxicological Sciences
Volume34
Issue number1
StatePublished - 1996

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Organ Culture Techniques
Acetaminophen
Toxicity
Kidney
Proteins
Carrier Proteins
Chemical activation
Antipyretics
Laboratory Animals
Analgesics
Animals
Adenosine Triphosphate
Association reactions

ASJC Scopus subject areas

  • Toxicology

Cite this

Hoivik, D. J., Fisher, R. L., Brendel, K., Gandolfi, A. J., Khairallah, E. A., & Cohen, S. D. (1996). Protein arylation precedes acetaminophen toxicity in a dynamic organ slice culture of mouse kidney. Toxicological Sciences, 34(1), 99-104.

Protein arylation precedes acetaminophen toxicity in a dynamic organ slice culture of mouse kidney. / Hoivik, Debie J.; Fisher, Robyn L.; Brendel, Klaus; Gandolfi, A Jay; Khairallah, Edward A.; Cohen, Steven D.

In: Toxicological Sciences, Vol. 34, No. 1, 1996, p. 99-104.

Research output: Contribution to journalArticle

Hoivik, DJ, Fisher, RL, Brendel, K, Gandolfi, AJ, Khairallah, EA & Cohen, SD 1996, 'Protein arylation precedes acetaminophen toxicity in a dynamic organ slice culture of mouse kidney', Toxicological Sciences, vol. 34, no. 1, pp. 99-104.
Hoivik, Debie J. ; Fisher, Robyn L. ; Brendel, Klaus ; Gandolfi, A Jay ; Khairallah, Edward A. ; Cohen, Steven D. / Protein arylation precedes acetaminophen toxicity in a dynamic organ slice culture of mouse kidney. In: Toxicological Sciences. 1996 ; Vol. 34, No. 1. pp. 99-104.
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