Methimazole-Induced Hepatotoxicity

Woeber, Kenneth A.

doi:10.4158/ep.8.3.222

Cited by 119 publications

(71 citation statements)

References 7 publications

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“…MMZ-induced olfactory deficits have also been reported in human patients (Bandyopadhyay et al, 2002;Woeber, 2002). In mice, cytochrome P450 (P450)-catalyzed MMZ metabolic activation is believed to be involved in MMZ's tissue toxicity, given the observation that pretreatment of mice with P450 inhibitors can suppress MMZ toxicity in both liver and OM (Brittebo, 1995;Mizutani et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

The Tissue-Specific Toxicity of Methimazole in the Mouse Olfactory Mucosa Is Partly Mediated through Target-Tissue Metabolic Activation by CYP2A5

Xie¹,

Zhou²,

Genter³

et al. 2011

Drug Metab Dispos

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ABSTRACT:The antithyroid drug methimazole (MMZ) can cause severe, tissuespecific toxicity in mouse olfactory mucosa (OM), presumably through a sequential metabolic activation of MMZ by cytochrome P450 (P450) and flavin monooxygenases (FMO). The aims of this study were to determine whether CYP2A5, one of the most abundant P450 enzymes in the mouse OM, is involved in MMZ metabolic activation, by comparing Cyp2a5-null with wild-type (WT) mice, and whether hepatic microsomal P450 enzymes, including CYP2A5, are essential for MMZ-induced OM toxicity, by comparing liver-Cpr-null (LCN) mice, which have little P450 activity in hepatocytes, with WT mice. We showed that the loss of CYP2A5 expression did not alter systemic clearance of MMZ (at 50 mg/kg, i.p.); but it did significantly decrease the rates of MMZ metabolism in the OM, whereas FMO expression in the OM was not reduced. MMZ induced depletion of nonprotein thiols, as well as pathological changes, in the OM of WT mice; the extent of these changes was much reduced in the Cyp2a5-null mice. Thus, CYP2A5 plays an important role in mediating MMZ toxicity in the OM. In contrast, the rate of systemic clearance of MMZ was significantly reduced in the LCN mice, compared to WT mice, whereas the MMZ-induced OM toxicity was not prevented. Therefore, hepatic P450 enzymes are essential for systemic MMZ clearance, but they are not required for MMZ-induced OM toxicity. We conclude that the tissue-specific toxicity of MMZ is mediated by target tissue metabolic activation, and the reaction is partly catalyzed by CYP2A5 in the OM.

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Section: Introductionmentioning

confidence: 99%

The Tissue-Specific Toxicity of Methimazole in the Mouse Olfactory Mucosa Is Partly Mediated through Target-Tissue Metabolic Activation by CYP2A5

Xie¹,

Zhou²,

Genter³

et al. 2011

Drug Metab Dispos

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“…Thyroid hormones might also have a direct toxic effect on hepatic tissue 6 . A common reason for co-existence of thyrotoxicosis and jaundice is liver injury induced by several medications, including thionamides which are used in the treatment of hypertoxicosis [7][8][9][10] . This was not the case with all our cases as they were not previously diagnosed with thyrotoxicosis and had not received antithyroid medications prior to presentation.…”

Section: Discussionmentioning

confidence: 99%

A report of three cases of jaundice with thyrotoxicosis

Akande¹,

Wo²

2013

Afr H. Sci.

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Background: Jaundice and hepatic dysfunction have been reported in patients with thyrotoxicosis and could be due to different mechanisms. Objective: To describe three cases of jaundice occurring in patients with thyrotoxicosis and to illustrate the importance of early institution of thionamides when indicated. Methods: We present the clinical and laboratory features of three patients presenting within a year with thyrotoxicosis and jaundice and whose clinical conditions improved remarkably following treatment with thionamides. In addition, current literature on the subject is reviewed and summarised. Results: The three patients presented with goitre and jaundice. None of the patients had received blood products, undergone scarification markings or experienced any previous episode of jaundice. Thyroid function tests in the three patients were consistent with a diagnosis of thyrotoxicosis. Liver function tests showed elevated bilirubin and transaminases. All patients improved remarkably following treatment with thionamides. Conclusion: It is important to rule out thyrotoxicosis in patients with jaundice of unknown cause and consider early use of thionamides for treatment of the thyrotoxicosis, if confirmed.

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“…These results are in accordance with what others have observed in animals and humans. Five percent of patients with hyperthyroidism treated with antithyroid drugs, including methimazole, are reported to have liver (Casallo Blanco et al, 2007;Woeber, 2002), lung (Tsai et al, 2001) and kidney damage (Calañas-Continente et al, 2005). The methimazole-caused hypothyroidism in animals has tumorigenic effects (Jemec, 1977) and modifies the pulmonary function (Liu & Ng, 1991).…”

Section: Hypothyrodism and The Ros-steady Statementioning

confidence: 99%