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Cytotoxic effects of N-hydroxyparacetamol in suspsensions of isolated rat hepatocytes.

Authors
  • Holme, J A
  • Wirth, P J
  • Dybing, E
  • Thorgeirsson, S S
Type
Published Article
Journal
Acta pharmacologica et toxicologica
Publication Date
Aug 01, 1982
Volume
51
Issue
2
Pages
87–95
Identifiers
PMID: 7113725
Source
Medline
License
Unknown

Abstract

The cytotoxicity of N-hydroxyparacetamol (N-OH-pHAA), a postulated proximate metabolite of the hepatotoxic and nephrotoxic analgesic paracetamol, was studied in suspensions of hepatocytes isolated by collagen-perfusion of livers of male rats. Incubation of cells with 0.25-2.0 mM N-OH-pHAA led after 3-5 hours to increased cell permeability measured by increased trypan blue uptake, increased NADH penetration or leakage of prelabelled 51Cr. N-OH-pHAA rapidly depleted cellular glutathione, 16% of initial levels were seen after 30 min. incubation. 3H-N-OH-pHAA bound covalently to cellular proteins in a time- and concentration-dependent manner, considerably higher binding rates were seen with boiled cells compared to intact cells. Pretreatment of animals with the cytochrome P-450 inducer phenobarbital did not affect N-OH-pHAA cytotoxicity or covalent binding, whereas the cytochrome P-450 inhibitor metyrapone inhibited both cytotoxicity and binding. Lipid peroxidation in hepatocytes could be seen as a limited range of N-OH-pHAA concentrations. In contrast, lipid peroxidation was an early event in cells exposed to carbon tetrachloride. A minimal exposure time of 30 min. of the hepatocytes to N-OH-pHAA was sufficient to elicit cellular damage occurring after 3-5 hours.

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