methimazole and Necrosis

Two cases of propylthiouracil-associated acute hepatitis, one case of fatal methimazole-associated hepatocellular necrosis and one case of propylthiouracil-associated lupus-like syndrome are described. The literature related to antithyroid drug side effects and the mechanisms for their occurrence are reviewed and the efficacy and complications of thyroidectomy and radioiodine compared to those of antithyroid drugs. It is concluded that in most circumstances 131I is the therapy of choice for hyperthyroidism.

Topics: Adult; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Lupus Erythematosus, Systemic; Methimazole; Necrosis; Propylthiouracil

It has been demonstrated that trimethylamine N-oxide (TMAO) serves as a driver of atherosclerosis, suggesting that reduction of TMAO level might be a potent method to prevent the progression of atherosclerosis. Herein, we explored the role of TMAO in the stability of carotid atherosclerotic plaques and disclosed the underlying mechanisms. The unstable carotid artery plaque models were established in C57/BL6 mice. L-carnitine (LCA) and methimazole (MMI) administration were applied to increase and reduce TMAO levels. Hematoxylin and eosin (H&E) staining, Sirius red, Perl's staining, Masson trichrome staining and immunohistochemical staining with CD68 staining were used for histopathology analysis of the carotid artery plaque. M1 and M2 macrophagocyte markers were assessed by RT-PCR to determine the polarization of RAW264.7 cells. MMI administration for 2 weeks significantly decreased the plaque area, increased the thickness of the fibrous cap and reduced the size of the necrotic lipid cores, whereas 5-week of administration of MMI induced intraplate hemorrhage. LCA treatment further deteriorated the carotid atherosclerotic plaque but with no significant difference. In mechanism, we found that TMAO treatment impaired the M2 polarization and efferocytosis of RAW264.7 cells with no obvious effect on the M1 polarization. In conclusion, the present study demonstrated that TMAO reduction enhanced the stability of carotid atherosclerotic plaque through promoting macrophage M2 polarization and efferocytosis.

Topics: Animals; Carotid Arteries; Carotid Artery Diseases; Disease Models, Animal; Down-Regulation; Enzyme Inhibitors; Fibrosis; Humans; Jurkat Cells; Macrophages; Male; Methimazole; Methylamines; Mice; Mice, Inbred C57BL; Mice, Knockout, ApoE; Necrosis; Oxygenases; Phagocytosis; Phenotype; Plaque, Atherosclerotic; RAW 264.7 Cells

Liver injury is a deleterious adverse effect associated with methimazole administration, and reactive intermediates are suspected to be involved in this complication. Glyoxal is an expected reactive intermediate produced during methimazole metabolism. Current investigation was undertaken to evaluate the role of carnosine, metformin, and N-acetyl cysteine as putative glyoxal (carbonyl) traps, against methimazole-induced hepatotoxicity. Methimazole (100 mg/kg, intraperitoneally) was administered to intact and/or glutathione (GSH)-depleted mice and the role of glyoxal trapping agents was investigated. Methimazole caused liver injury as revealed by an increase in serum alanine aminotransferase and aspartate aminotransferase. Moreover, lipid peroxidation and protein carbonylation occurred significantly in methimazole-treated animals' liver. Hepatic GSH reservoirs were decreased, and inflammatory cells infiltration was observed in liver histopathology. Methimazole-induced hepatotoxicity was severe in GSH-depleted mice and accompanied with interstitial hemorrhage and necrosis of the liver. Glyoxal trapping agents effectively diminished methimazole-induced liver injury both in intact and/or GSH-depleted animals.

Topics: Acetylcysteine; Alanine Transaminase; Animals; Aspartate Aminotransferases; Carnosine; Chemical and Drug Induced Liver Injury; Male; Metformin; Methimazole; Mice; Necrosis; Oxidative Stress; Protective Agents

Experiments with 130 outbred male rats weighing 220-250 g have show that stress "free swimming in a cage" (FSC) affects the histological structure of the liver as early as in 1 h. FSC occurred in standard plastic cages (5 animals) filled with water to a height of 15 cm and topped with a grid. One hour after FSC (the alarm-stage) caused dystrophy of hepatocytes and increased blood flow to the liver lobules, which also continued at the resistance-stage (48 h after the FSC). At the exhaustion-stage (daily 1-hour stress for 10 days) there were even greater hepatocytes dystrophy, necrosis, and their microcirculatory disturbances in the lobules. The introduction of merkazolil (intragastrically 25 mg/kg for 20 days) per se altered the histostructure of the liver tissue and under stress aggravates the microcirculatory changes, dystrophy and necrosis of the hepatocytes. Small doses of L-thyroxine (intragastrically 1.5-3.0 μg/kg for 28 days) minimized the histological signes of the liver damage at all stages of the stress response. Consequently, the iodine-containing thyroid hormones limit the disturbance of the microstructure of the liver caused by stress.

Topics: Animals; Animals, Outbred Strains; Antithyroid Agents; Hepatocytes; Liver; Liver Circulation; Male; Methimazole; Necrosis; Rats; Stress, Physiological; Swimming; Thyroid Gland; Thyroxine; Time Factors

Topics: Adult; Female; Follow-Up Studies; Goiter; Humans; Intraoperative Complications; Methimazole; Necrosis; Plastic Surgery Procedures; Surgical Flaps; Surgical Wound Infection; Thyroid Crisis; Trachea; Treatment Outcome

Thyroid destruction leading to endemic myxoedematous cretinism is highly prevalent in central Africa, where iodine (I) and selenium (SE) deficiencies as well as thiocyanate (SCN) overload are combined. All three factors have been studied experimentally in the etiology of the disease, but they have never been studied in combination. In a model using rats, we have previously shown that combining I and SE deficiencies increases the sensitivity of the thyroid to necrosis after iodide overload, an event unlikely to occur in the African situation. To develop a model that would more closely fit with the epidemiological findings, we have determined whether an SCN overload would also result in thyroid necrosis as does the I overload. The combination of the three factors increased by 3.5 times the amount of necrotic cells, from 5.5 +/- 0.3% in the I-SE+ thyroids to 18.9 +/- 1.6% in the I-SE-SCN-overloaded ones. Methimazole administration prevented the SCN-induced necrosis. SE- thyroids evolved to fibrosis, whereas SE+ thyroids did not. TGFbeta was prominent in macrophages present in SE- glands. Thyroid destruction in central Africa might therefore originate from the interaction of three factors: I and SE deficiencies by increasing H(2)O(2) accumulation, SE deficiency by decreasing cell defense and promoting fibrosis, and SCN overload by triggering follicular cell necrosis.

Topics: Africa, Central; Animals; Antithyroid Agents; Congenital Hypothyroidism; Disease Models, Animal; Endemic Diseases; Female; Fibrosis; Hydrogen Peroxide; Inflammation; Iodine; Macrophages; Methimazole; Myxedema; Necrosis; Perchlorates; Rats; Rats, Wistar; Selenium; Sodium Compounds; Thiocyanates; Thyroid Gland; Transforming Growth Factor beta

Apoptosis, necrosis, and cell proliferation induced by S-(1,2-dichlorovinyl)-L-cysteine (DCVC), the cysteine conjugate of the environmental and occupational contaminant trichloroethylene, were studied in primary cultures of human proximal tubular (hPT) cells. Cells from male and female donors were incubated with a range of concentrations of DCVC (10 to 1000 microM) for up to 48 h, and assessments of cellular morphology (phase-contrast microscopy), necrosis (lactate dehydrogenase (LDH) release), apoptosis(cell cycle analysis, annexin V staining, and caspase activation), and proliferation (cell cycle analysis and DNA synthesis) were made. Time- and concentration-dependent changes in cellular morphology, including elongation of cell shape, formation of intracellular vesicles, and formation of apoptotic bodies, were observed. Significant increases in LDH release occurred in hPT cells incubated with < or =100 microM DCVC for at least 24 h. hPT cells from males were modestly more sensitive to DCVC than those from females, with maximal LDH release of 78 and 65% in cells from males and females, respectively. Flow cytometry analysis of propidium iodide-stained and DCVC-treated hPT cells showed that apoptosis occurred at markedly lower concentrations (10 microM) and at much earlier incubation times (2 h) than necrosis. A small increase was also noted in the percentage of cells in S-phase after a 4-h treatment with as little as 10 microM DCVC, suggesting that cell proliferation was stimulated. This was supported further by increased DNA synthesis. These results show that DCVC causes apoptosis and enhances cell proliferation in hPT cells at environmentally relevant doses and at earlier time points and lower concentrations than necrosis.

Topics: Adult; Aged; Annexin A5; Apoptosis; Caspases; Cell Cycle; Cell Division; Cell Survival; Cells, Cultured; Cysteine; DNA; Dose-Response Relationship, Drug; Female; Flow Cytometry; Humans; Kidney Tubules, Proximal; L-Lactate Dehydrogenase; Male; Methimazole; Microscopy, Confocal; Middle Aged; Necrosis; Tacrolimus; Time Factors

In mice depleted of GSH by treatment with buthionine sulfoximine (BSO), methimazole (2-mercapto-1-methylimidazole, MMI) causes liver injury characterized by centrilobular necrosis of hepatocytes and an increase in serum alanine transaminase (SALT) activity. MMI requires metabolic activation by both P450 monooxygenase and flavin-containing monooxygenase (FMO) before it produces the hepatotoxicity. MMI and its analogues were examined for the ability to increase SALT activity in GSH-depleted mice. Saturation of the C-4,5 double bond in MMI resulted in a complete loss of hepatotoxicity. Similarly, ring fusion of a benzene nucleus to the C-4,5 double bond, forming 2-mercapto-1-methylbenzimidazole, abolished the toxic potency. As for MMI, 2-mercapto-1,4,5-trimethylimidazole, and 2-mercapto-1-methyl-4, 5-di-n-propylimidazole, the toxic potency decreased with the increasing bulk of the 4- and 5-alkyl substituents. Furthermore, methylation of the thiol group of MMI totally reduced its toxicity. These structural requirements and the known toxicity of thiono-sulfur compounds led us to the hypothesis that MMI would undergo epoxidation of the C-4,5 double bond by P450 enzymes and, after being hydrolyzed, the resulting epoxide would be then decomposed to form N-methylthiourea, a proximate toxicant. Before N-methylthiourea would produce toxicity, it would be further biotransformed to its S-oxidized metabolites mainly by FMO. Evidence for this hypothesis was provided by the facts that N-methylthiourea and glyoxal as the accompanying fragment were identified as urinary metabolites in mice treated with MMI and that N-methylthiourea caused a marked increase in SALT activity when administered to mice in combination with BSO.

Topics: Animals; Buthionine Sulfoximine; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Gas Chromatography-Mass Spectrometry; Glutathione; Liver; Male; Methimazole; Mice; Mice, Inbred ICR; Necrosis; Structure-Activity Relationship; Thiourea

Methimazole, an anti-thyroid drug, was recently found to be useful in the treatment of systemic lupus erythematosus and other autoimmune diseases. Moreover, decreased thyroid hormone production is associated with a variety of immunological manifestations, such as reduced activation of CD4+ cells, increased CD8+ cell activity and reduced soluble IL-2 receptors. In the present study we examined the effects of methimazole and propylthiouracil on a rat model of experimental colitis.. Colitis was induced by intracolonic administration of 30 mg trinitrobenzene sulphonic acid (TNB). Two weeks prior to induction of colitis, rats were treated by either methimaziole (0.04%) or propylthiouracil (0.01%) in drinking water after a week of free access to water. Rats were sacrificed 48 h or 7 days after induction of colitis. The colon was isolated, rinsed with ice-cold water and weighed. Damage was assessed both macroscopically and microscopically and myeloperoxidase (MPO) activity determined.. All treated rats were hypothyroid as manifested by a significant elevation of thyroid stimulating hormone (TSH), by comparison with the control groups (mean -1.82 +/- 0.40 versus 0.11 +/- 0.02 mmol/L, respectively). The inflammatory response elicited by TNB resulted in severe mucosal damage 48 h after damage induction, which persisted for 7 days. Pre-treatment with either methimazole 0.04% or propylthiouracil 0.01% significantly decreased mucosal damage macroscopically (lesion area, lesion score and segmental weight) microscopically and also significantly decreased MPO level at both time points (P < 0.01).. Methimazole and propylthiouracil significantly reduce mucosal damage and colonic weight in a rat model of colitis. The mode by which they do so remains to be studied.

Topics: Animals; Antithyroid Agents; Colitis, Ulcerative; Intestinal Mucosa; Male; Methimazole; Necrosis; Peroxidase; Propylthiouracil; Rats; Rats, Inbred Strains; Trinitrobenzenesulfonic Acid