Effect of deferrioxamine and diethyldithiocarbamate on paracetamol-induced hepato- and nephrotoxicity. The role of lipid peroxidation.
In mice subjected to glutathione depletion by pretreatment with phorone (diisopropylidene acetone, 200 mg/kg i.p. in 10 ml/kg olive oil) paracetamol (acetaminophen, 300 mg/kg p.o. in 10 ml/kg tylose 2 h later) led to a marked hepatotoxicity as evidenced by increased plasma activities of the liver-specific enzymes sorbitol dehydrogenase (SDH) and glutamate-pyruvate-transaminase (GPT) 3 and 24 h after treatment. Nephrotoxicity was also indicated at both timepoints by an increased creatinine concentration in plasma, while neither the urine volume nor its content in gamma-glutamyl transpeptitase over 20 h were affected. Hepato- and nephrotoxicity were also assessed histomorphologically. In vivo lipid peroxidation (LPO), as measured by ethane exhalation over 3 h, was clearly enhanced by paracetamol. Malondialdehyde content was increased and glutathione concentration diminished in the liver, but not in the kidney. Diethyldithiocarbamate (DTC, 200 mg/kg i.p.) or deferrioxamine (DFO, 500 mg/kg i.p.) both given 30 min before PA, inhibited in vivo LPO. However, only DTC was capable of antagonizing the hepato- and nephrotoxic effects of paracetamol, while DFO only delayed the onset of nephrotoxicity but left the hepatotoxicity unaffected. Both agents inhibited the rise in hepatic malondialdehyde-content, but only DTC prevented paracetamol-induced glutathione depletion. These results indicate that LPO is not mainly responsible for paracetamol toxicity towards liver or kidney.
Younes
M
M
Institute of Toxicology, Medical University of Lübeck, FRG.
Sause
C
C
Siegers
C P
CP
Lemoine
R
R
D000082:Acetaminophen / Q000494:pharmacology*; D000818:Animals; D003404:Creatinine / Q000032:analysis; D003676:Deferoxamine / Q000494:pharmacology*; D004050:Ditiocarb / Q000494:pharmacology*; D004980:Ethane / Q000032:analysis; D005978:Glutathione / Q000032:analysis; D007668:Kidney / Q000032:analysis / Q000187:drug effects*; D008054:Lipid Peroxides / Q000096:biosynthesis*; D008099:Liver / Q000032:analysis / Q000187:drug effects*; D008297:Male; D008315:Malondialdehyde / Q000032:analysis; D051379:Mice
D008054:Lipid Peroxides; D000082:Acetaminophen; D008315:Malondialdehyde; D004050:Ditiocarb; D003404:Creatinine; D005978:Glutathione; D003676:Deferoxamine; D004980:Ethane