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Effect of diltiazem on acetaminophen and phalloidine hepatotoxicity
1Département de Pharmacologie, Faculté de Médecine, Université de Montréal, Québec.
Abstract:
The protective effect of diltiazem on acetaminophen and phalloidine hepatotoxicity has been studied in male CD-1 mice. Groups of 8 mice each received 0.9% NaCl or 6, 12, 18 and 24 mg/kg of diltiazem 20 minutes after 750 mg/kg of acetaminophen and were sacrificed 24 hours later to assess liver toxicity. Dosages of at least 12 mg/kg were required to prevent the increase in alanine transaminase (ALT) and only the 24 mg/kg hindered the appearance of histological lesions. ALT remained close to control values 48 hours after the administration of the 24 mg/kg dose of diltiazem. Diltiazem was less effective in preventing hepatotoxicity when administered 3 hours after acetaminophen. Diltiazem (24 mg/kg) reduced the increase in ALT induced by 1.1 mg/kg of phalloidine by 58% (4460 +/- 317 U/mL v.s. 1852 +/- 339 U/mL; p less than 0.05). It is concluded that high doses of diltiazem, administered early after the toxicant, prevent hepatic toxicity of acetaminophen but produce only a modest effect on phalloidine hepatotoxicity.
Insights
High doses of diltiazem can protect the liver from acetaminophen toxicity when given soon after exposure. However, diltiazem shows limited effectiveness against phalloidine-induced liver damage.
Area of Science:
- Hepatology
- Pharmacology
- Toxicology
Background:
- Acetaminophen and phalloidine are known hepatotoxins.
- Diltiazem is a calcium channel blocker with potential protective properties.
Purpose of the Study:
- To investigate the protective effects of diltiazem against acetaminophen and phalloidine-induced liver toxicity in mice.
- To determine the efficacy of diltiazem based on dosage and timing of administration.
Main Methods:
- Male CD-1 mice were administered acetaminophen (750 mg/kg) or phalloidine (1.1 mg/kg).
- Diltiazem (6-24 mg/kg) was administered at different time points post-toxicant exposure.
- Liver toxicity was assessed by measuring alanine transaminase (ALT) levels and examining histological lesions.
Main Results:
- Diltiazem doses of at least 12 mg/kg prevented ALT increase after acetaminophen.
- A 24 mg/kg dose of diltiazem hindered histological lesions and maintained normal ALT levels for 48 hours.
- Diltiazem was less effective when administered 3 hours after acetaminophen.
- Diltiazem (24 mg/kg) reduced phalloidine-induced ALT increase by 58%.
Conclusions:
- High-dose diltiazem, administered early, effectively prevents acetaminophen-induced hepatotoxicity.
- Diltiazem demonstrates a modest protective effect against phalloidine-induced hepatotoxicity.
- Timing of diltiazem administration is crucial for its efficacy in preventing liver injury.