Renal necrosis, glutathione depletion, and covalent binding after acetaminophen

Randolph J. McMurtry, Wayne R. Snodgrass, Jerry R. Mitchell

Research output: Contribution to journalArticle

195 Citations (Scopus)

Abstract

A dose-dependent, acute renal necrosis occurred in male Fischer rats following a single subcutaneous injection of acetaminophen. Doses of [3H]acetaminophen (750-900 mg/kg) causing renal and hepatic necrosis in rats markedly depleted target organ glutathione and resulted in large amounts of radiolabeled metabolite being bound to renal and hepatic protein. Pretreatment with cobalt chloride, an inhibitor of hepatic and renal drug metabolism, decreased both the irreversible binding of metabolite and the glutathione depletion in target organ tissues while concomitantly protecting against tissue damage. Pretreatment with 3-methylcholanthrene enhanced hepatic necrosis and covalent binding of metabolite to hepatic protein in vivo and to microsomal protein in vitro but had little effect on the corresponding renal parameters. Covalent binding of radiolabeled acetaminophen to rat renal or hepatic microsomes was enzyme dependent and required NADPH and oxygen. Thus, acetaminophen-induced renal and hepatic necrosis apparently result from in situ activation of acetaminophen to a chemically reactive species capable of covalently binding to target organ macromolecules.

Original languageEnglish (US)
Pages (from-to)87-100
Number of pages14
JournalToxicology and Applied Pharmacology
Volume46
Issue number1
DOIs
StatePublished - 1978
Externally publishedYes

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Acetaminophen
Glutathione
Necrosis
Kidney
Metabolites
Liver
Rats
Tissue
Proteins
Methylcholanthrene
Macromolecules
NADP
Metabolism
Inbred F344 Rats
Chemical activation
Subcutaneous Injections
Microsomes
Oxygen
Enzymes
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Renal necrosis, glutathione depletion, and covalent binding after acetaminophen. / McMurtry, Randolph J.; Snodgrass, Wayne R.; Mitchell, Jerry R.

In: Toxicology and Applied Pharmacology, Vol. 46, No. 1, 1978, p. 87-100.

Research output: Contribution to journalArticle

McMurtry, Randolph J. ; Snodgrass, Wayne R. ; Mitchell, Jerry R. / Renal necrosis, glutathione depletion, and covalent binding after acetaminophen. In: Toxicology and Applied Pharmacology. 1978 ; Vol. 46, No. 1. pp. 87-100.
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