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Deoxyribonuclease 1 aggravates acetaminophen‐induced liver necrosis in male CD‐1 mice
Author(s) -
Napirei Markus,
Basnakian Alexei G.,
Apostolov Eugene O.,
Mannherz Hans Georg
Publication year - 2006
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.21034
Subject(s) - acetaminophen , necrosis , glutathione , nad+ kinase , liver injury , metabolite , dna damage , chemistry , microbiology and biotechnology , biochemistry , biology , pharmacology , medicine , enzyme , dna
An overdose of acetaminophen (APAP) ( N ‐acetyl‐p‐aminophenol) leads to hepatocellular necrosis induced by its metabolite N ‐acetyl‐p‐benzoquinone‐imine, which is generated during the metabolic phase of liver intoxication. It has been reported that DNA damage occurs during the toxic phase; however, the nucleases responsible for this effect are unknown. In this study, we analyzed the participation of the hepatic endonuclease deoxyribonuclease 1 (DNASE1) during APAP‐induced hepatotoxicity by employing a Dnase1 knockout (KO) mouse model. Male CD‐1 Dnase1 wild‐type (WT) ( Dnase1 +/+ ) and KO ( Dnase1 −/− ) mice were treated with 2 different doses of APAP. Hepatic histopathology was performed, and biochemical parameters for APAP metabolism and necrosis were investigated, including depletion of glutathione/glutathione‐disulfide (GSH+GSSG), β‐nicotinamide adenine dinucleotide (NADH+NAD + ), and adenosine triphosphate (ATP); release of aminotransferases and Dnase1; and occurrence of DNA fragmentation. As expected, an APAP overdose in WT mice led to massive hepatocellular necrosis characterized by the release of aminotransferases and depletion of hepatocellular GSH+GSSG, NADH+NAD + , and ATP. These metabolic events were accompanied by extensive DNA degradation. In contrast, Dnase1 KO mice were considerably less affected. In conclusion , whereas the innermost pericentral hepatocytes of both mouse strains underwent necrosis to the same extent independent of DNA damage, the progression of necrosis to more outwardly located cells was dependent on DNA damage and only occurred in WT mice. Dnase1 aggravates APAP‐induced liver necrosis. (H EPATOLOGY 2006;43:297–305.)