Extensive alteration of genomic DNA and rise in nuclear Ca2+ in vivo early after hepatotoxic acetaminophen overdose in mice.
Hepatotoxic doses of acetaminophen cause early impairment of Ca2+ homeostasis. In this in vivo study, 600 mg/kg acetaminophen caused total nuclear Ca2+ and % fragmented DNA to rise in parallel from 2-6 hr, followed by large later increases mirroring frank liver injury. Agarose gel electrophoresis revealed substantial loss of large genomic DNA from 2 hours onward, with accumulation of DNA fragments in a ladder-like pattern resembling apoptosis. Extensive late cleavage of DNA probably resulted from cell death, whereas degradative loss of large genomic DNA at 2 hours arose at an early enough point to contribute to acetaminophen-induced liver necrosis in mice.
Ray
S D
SD
Toxicology Program, College of Pharmacy, University of New Mexico, Albuquerque 87131.
Sorge
C L
CL
Tavacoli
A
A
Raucy
J L
JL
Corcoran
G B
GB
D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice
D000082:Acetaminophen; D002118:Calcium