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Paradoxical effect of methimazole on liver mitochondria: In vitro and in vivo
Hossein Niknahad1, Akram Jamshidzadeh1, Reza Heidari2
1Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Pharmacology and Toxicology Department, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
Abstract:
Methimazole is the most frequently prescribed antithyroid agent. On the other hand, several cases of liver injury are attributed to this drug. The mechanism of methimazole-induced liver injury is obscure. Hepatocytes mitochondria seem to be a target for methimazole cytotoxicity. Current investigation aimed to evaluate the effects of methimazole on the hepatocytes mitochondria in different experimental models. In the in vivo model, methimazole (100, 200 and 400mg/kg, i.p) was administered to mice and liver mitochondria were isolated and assessed. In the in vitro experiments, intact isolated liver mitochondria were incubated with increasing methimazole concentrations (10μM-100mM). It was found that methimazole decreased liver mitochondrial ATP and glutathione, increased mitochondrial swelling, lipid peroxidation and reactive oxygen species (ROS), and collapsed mitochondrial membrane potential when administered to mice. Paradoxically, methimazole not only caused no significant injury toward isolated liver mitochondria in vitro but improved mitochondrial function and protected this organelle. The differences between two investigated models in the current study might be associated with drug bioactivation and reactive metabolites formation. These findings suggest mitochondrial dysfunction as a mechanism for methimazole-induced liver injury. Moreover, methimazole seems to be a novel mitochondrial protecting agent in vitro.
Insights
Methimazole, a common antithyroid drug, causes liver injury by damaging liver mitochondria in mice. Paradoxically, it protects mitochondria in lab tests, suggesting complex drug interactions.
Area of Science:
- Hepatology
- Mitochondrial Biology
- Pharmacology
Background:
- Methimazole is a primary antithyroid medication.
- Liver injury is a known adverse effect of methimazole.
- The precise mechanism of methimazole-induced liver injury remains unclear.
Purpose of the Study:
- To investigate the effects of methimazole on liver mitochondria.
- To explore the potential role of mitochondria in methimazole-induced liver injury.
Main Methods:
- In vivo studies involved administering methimazole to mice and isolating liver mitochondria.
- In vitro studies incubated isolated liver mitochondria with varying methimazole concentrations.
- Mitochondrial function was assessed by measuring ATP, glutathione, swelling, lipid peroxidation, ROS, and membrane potential.
Main Results:
- In vivo, methimazole decreased ATP and glutathione, increased swelling, lipid peroxidation, and ROS, and collapsed mitochondrial membrane potential.
- In vitro, methimazole did not injure isolated mitochondria and even improved their function.
- Differences between in vivo and in vitro results may stem from drug bioactivation and reactive metabolite formation.
Conclusions:
- Mitochondrial dysfunction is a likely mechanism underlying methimazole-induced liver injury.
- Methimazole may act as a mitochondrial protective agent in vitro, highlighting context-dependent effects.
