Chromatin breakdown by deoxyribonuclease1 promotes acetaminophen-induced liver necrosis: an ultrastructural and histochemical study on male CD-1 mice.
We analyzed in male wild-type (WT) and Dnase1 knockout (KO) CD-1 mice after acetaminophen (APAP)-intoxication the hepatolobular distribution of APAP-adducts in relation to DNA-damage by terminal deoxyribonucleotidyl-transferase dUTP nick end-labeling (TUNEL), the ultrastructural alterations of hepatocellular morphology and the intracellular localization of Dnase1. Treatment of WT-mice with 600 mg/kg APAP led to extensive pericentral necrosis. Electron microscopy (EM) demonstrated vesiculation of the rough endoplasmatic reticulum and swelling of mitochondria. Pericentral WT-hepatocyte nuclei exhibited pyknosis, karyorrhexis and karyolysis. In contrast, livers from treated KO-mice exhibited almost normal light microscopical structure and EM revealed only mild signs of hepatocellular damage. In WT-mice several layers of pericentral hepatocytes displayed APAP-adduct formation and subsequent DNA-damage, whereas in KO-animals only few cells were affected. Serum aminotransferases rose similarly in both mouse strains up to 12 h, thereafter increased only in WT-mice. Immunogold-EM revealed the translocation of Dnase1 from the rER into the nuclei of treated WT-mice. In KO-mice, APAP-adduct formation was retarded and less extensive suggesting that detoxification of APAP must have been more effective in KO-mice possibly due to the lack of energy depletion otherwise caused by Dnase1-induced DNA-damage in WT-mice.
Jacob
Monika
M
Abteilung für Anatomie und Embryologie, Medizinische Fakultät, Ruhr-Universität Bochum, Universitätsstrasse 150, 44801 Bochum, Germany. monika.jacob@rub.de
Mannherz
Hans Georg
HG
Napirei
Markus
M
D000082:Acetaminophen / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D002843:Chromatin / Q000378:metabolism*; D003850:Deoxyribonuclease I / Q000378:metabolism*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008099:Liver / Q000473:pathology* / Q000648:ultrastructure; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis
D018712:Analgesics, Non-Narcotic; D002843:Chromatin; D000082:Acetaminophen; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D003850:Deoxyribonuclease I