Early sustained rise in total liver calcium during acetaminophen hepatotoxicity in mice.
This investigation sought evidence of impaired calcium regulation occurring early during acetaminophen-induced hepatotoxicity and signs of a close temporal relationship between the onset of arylation damage and impaired ion regulation. Acetaminophen produced a dose-related accumulation of calcium at 4 hr but this increase was highly variable when expressed relative to liver protein content. Reporting calcium content per total liver or liver calcium per unit total body weight reduced the coefficient of variation from 34% to less than 9% by acknowledging the accumulation of protein and the rise in organ weight which accompany liver injury. This allowed potentially toxic elevations in calcium concentration to be detected as early as 2 hr after acetaminophen overdose. These results document the early permanent disruption of calcium homeostasis and temporally link this disturbance with the onset of arylation damage, which appeared at 1.5 hr. Such findings support the hypothesis that acetaminophen covalent binding represents a biochemical lesion that is capable of disrupting calcium homeostasis and causing cell death. N-Acetylcysteine blocked calcium accumulation and abolished liver damage by acetaminophen. Mice sustaining necrosis were the only animals to display elevated liver calcium at 24 hr. These results point to interference in hepatic calcium regulation as an early event that may contribute to acetaminophen-induced injury and cell death in vivo.
Corcoran
G B
GB
Department of Pharmaceutics, School of Pharmacy, State University of New York, Buffalo 14260.
Wong
B K
BK
Neese
B L
BL
D000082:Acetaminophen / Q000633:toxicity*; D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D011506:Proteins / Q000378:metabolism; D013054:Spectrophotometry, Atomic; D013997:Time Factors
D011506:Proteins; D000082:Acetaminophen; D002118:Calcium; D000111:Acetylcysteine