Elsevier

Biochemical Pharmacology

Volume 28, Issue 13, 1 July 1979, Pages 2051-2055
Biochemical Pharmacology

Acute paracetamol intoxication of starved mice leads to lipid peroxidation in vivo

https://doi.org/10.1016/0006-2952(79)90223-5Get rights and content

Abstract

Lipid peroxidation was monitored in female mice in vivo by the measurement of exhalated hydrocarbons. In liver homogenates in vitro lipid peroxidation as determined by malondialdehyde formation, and hepatic total glutathione levels were measured. After a dose of 500 mg/kg i.p. of paracetamol, the hepatic glutathione of fed mice decreased from 61 nmoles/mg liver protein to 30 nmoles/mg, while the animals expired 5 nmoles of ethane/kga · hr. The same dose in starved mice led to a glutathione level of 6 nmoles/mg and an exhalation rate of 125–150 nmoles ethane/kg · hr. In vivo determined and post-mortem in vitro determined lipid peroxidation correlated with a coefficient of 0.66. If hepatic glutathione was depleted to the same extent by administration of diethylmaleate, no significant lipid peroxidation was found. Our findings demonstrate that the drug-induced depletion of liver glutathione leads in vivo to lipid peroxidation, provided that the glutathione level has been diminished by starvation. The data indicate that glutathione depletion alone by other mechanisms does not account for lipid peroxidation. Hence the hepatoprotective role of liver glutathione against drug-induced liver injury has to be reconsidered in detail. This investigation shows a suitable model for such studies.

References (25)

  • H. Sies et al.

    FEBS Lett.

    (1972)
  • U. Köster et al.

    Toxic. appl. Pharmac.

    (1977)
  • R.L. Heath et al.

    Biochem. biophys. Res. Commun.

    (1965)
  • J.E. Brehe et al.

    Analyt. Biochem.

    (1976)
  • A.G. Hildebrandt et al.

    Biochem. biophys. Res. Commun.

    (1973)
  • G.D. Nordblom et al.

    Archs Biochem. Biophys.

    (1977)
  • C. Richter et al.

    J. biol. Chem.

    (1977)
  • J.R. Mitchell et al.

    J. Pharmac. exp. Ther.

    (1973)
  • D.J. Jollow et al.

    J. Pharmac. exp. Ther.

    (1973)
  • W.Z. Potter et al.

    J. Pharmac. exp. Ther.

    (1973)
  • J.R. Gillette et al.

    A. Rev. Pharmac. Toxic.

    (1975)
  • G.L. Plaa et al.

    A. Rev. Pharmac. Toxic.

    (1976)
  • Cited by (256)

    • Detoxifying effect of pyridoxine on acetaminophen-induced hepatotoxicity via suppressing oxidative stress injury

      2018, Food and Chemical Toxicology
      Citation Excerpt :

      When detoxifying enzyme glutathione peroxidase (GPx) functions very inefficiently with rapid formation of free radicals, hepatocytes will be damaged due to oxidative stress (Dai and Cederbaum, 1995; Nakamura et al., 1974). Oxidative stress as measured by lipid peroxidation might be mechanistically important in APAP-induced hepatotoxicity (Hassoun et al., 2014; Noriega et al., 2000; Wendel et al., 1979). When NAPQI accumulates in the liverdue to GSH depletion, it can form adducts by covalently binding to hepatocellular proteins inside mitochondria, nucleus, and cytosolof hepatocytes and produce hepatotoxicity through hepatic necrosis (Kuralay et al., 1998; Yang et al., 2013).

    • Oxidative stress and acute hepatic injury

      2018, Current Opinion in Toxicology
      Citation Excerpt :

      An additional initiator of mitochondrial ROS generation could be lysosomal iron, which is released from disrupted lysosomes and taken up by mitochondria [19] through the calcium uniporter, generating hydroxyl radicals [20]. Though early studies had implicated lipid peroxidation in the process [21], this was later established to be due to the vitamin E-deficient diet the animals were subjected to, with very limited lipid peroxidation in animals on a normal diet [22]. In addition, there was no protection seen by vitamin E administration against APAP-induced liver injury in animals on a normal diet [22], ruling out a relevant role for lipid peroxidation in liver injury.

    • Medications with male reproductive side effects

      2018, Encyclopedia of Reproduction
    View all citing articles on Scopus
    View full text