title: Paradoxical effect of methimazole on liver mitochondria: In vitro and in vivo.
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.
authors: Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Pharmacology and Toxicology Department, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
authors: Hossein
authors: H
authors: Niknahad
authors: Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Pharmacology and Toxicology Department, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
authors: Akram
authors: A
authors: Jamshidzadeh
authors: Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address: rezaheidari@hotmail.com.
authors: Reza
authors: R
authors: Heidari
authors: Pharmacology and Toxicology Department, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
authors: Zeynab
authors: Z
authors: Hosseini
authors: Pharmacology and Toxicology Department, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
authors: Keivan
authors: K
authors: Mobini
authors: Pharmacology and Toxicology Department, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
authors: Forouzan
authors: F
authors: Khodaei
authors: Department of Animal Science, School of Agriculture, Shiraz University, Shiraz, Iran.
authors: Mohammad Mehdi
authors: MM
authors: Ommati
authors: Food and Drug Organization, Ministry of Health, Tehran, Iran.
authors: Narges
authors: N
authors: Abdoli
authors: Pharmacology and Toxicology Department, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
authors: Nahid
authors: N
authors: Keshavarz
authors: Students Research Committee, Shiraz University of Medical Sciences, International Branch, Shiraz, Iran.
authors: Mandana
authors: M
authors: Bazyari
authors: Pharmacology and Toxicology Department, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
authors: Asma
authors: A
authors: Najibi
mesh_terms: D000818:Animals; D013956:Antithyroid Agents / Q000633:toxicity*; D015415:Biomarkers / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008713:Methimazole / Q000633:toxicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D008930:Mitochondria, Liver / Q000187:drug effects*; D015394:Molecular Structure; D011897:Random Allocation
chemical_list: D013956:Antithyroid Agents; D015415:Biomarkers; D008713:Methimazole
keywords: Antithyroids hepatotoxicity; Glyoxal; Liver injury; Methimazole; Mitochondria