Potentiation of acetaminophen hepatotoxicity and mortality by doxapram in mice.
Whether a single dose of doxapram (DOP) can modulate the acute toxicity and the hepatotoxicity induced by acetaminophen (AA) was examined. Pretreatment with DOP (40 mg/kg, i.p.) 30 min prior to the administration of AA dose-dependently potentiated the lethality of AA in both native mice and mice fasted for 18 h, and the potentiating activity was greater in fasted mice than in native mice. The hepatotoxicity of AA was assessed by plasma transaminases activity (glutamyl oxaloacetic transaminase, GOT; glutamyl pyruvic transaminase, GPT) and the amount of plasma lipid peroxides at 6, 12, 18, 24, 36 and 48h after the administration of AA and histopathological examination of liver sections at 24 h after the administration of AA. DOP (40 mg/kg, i.p.) did not increase the plasma transaminase activity or the lipid peroxides level significantly, whereas AA administration to DOP-treated animals produced earlier maximal elevation of transaminase and lipid peroxide values compared to AA alone. These findings indicate that mortality and hepatotoxicity of AA is potentiated by DOP in mice.
Kanno
S
S
Department of Pharmacology and Toxicology, Cancer Research Institute, Tohoku College of Pharmacy, Sendai, Japan.
Ishikawa
M
M
Takayanagi
M
M
Takayanagi
Y
Y
Sasaki
K
K
D000082:Acetaminophen / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000818:Animals; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury; D004315:Doxapram / Q000633:toxicity*; D004357:Drug Synergism; D008297:Male; D051379:Mice; D019141:Respiratory System Agents / Q000633:toxicity*
D018712:Analgesics, Non-Narcotic; D000697:Central Nervous System Stimulants; D019141:Respiratory System Agents; D000082:Acetaminophen; D004315:Doxapram