Metabolism-dependent hepatotoxicity of methimazole in mice depleted of glutathione

Mizutani, Tetsuya; Murakami, Mihoko; Shirai, Mutsuko; Tanaka, Maki; Nakanishi, Kazuo

doi:10.1002/(sici)1099-1263(199905/06)19:3<193::aid-jat553>3.0.co;2-9

Cited by 43 publications

(32 citation statements)

References 24 publications

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“…A CYP-dependent metabolic activation of methimazole in the liver has previously been reported by Lee and Neal (20). Methimazole is also a known substrate for flavinecontaining monooxygenases (FMO) (25) and a recent study suggests that both CYP and FMO are involved in the hepatic metabolism of methimazole (23).…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies have shown that in vivo GSH-depletion can potentiate the olfactory toxicity of some compounds (2,7). In GSH-depleted mice, methimazole exposure will induce a centrilobular hepatic necrosis (23,24). The effects of methimazole on the morphology of the olfactory mucosa in GSH-depleted animals or the effect of methimazole on the level of GSH in the olfactory mucosa have not been reported, however.…”

Section: Introductionmentioning

confidence: 99%

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Methimazole-Induced Damage in the Olfactory Mucosa: Effects on Ultrastructure and Glutathione Levels

et al. 2003

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Methimazole is an antithyroid drug that can induce loss of smell and taste in humans. It is also an olfactory toxicant in rodents. The aim of the present study was to examine involvement of glutathione in methimazole-induced damage of the olfactory mucosa (OM) of mice, and to study early onset of this damage using transmission electron microscopy (TEM). We found that an intraperitoneal dose of methimazole induced a dose-dependent decrease of nonprotein sulfhydryl groups (NP-SH; mainly glutathione) in the OM. Hepatic NP-SH was not decreased. One hour after administration (50 mg/kg), TEM demonstrated an extensive damage to acinar and intraepithelial excretory duct cells of Bowman's glands (BG) including dilatation of the endoplasmic reticulum and mitochondrial swelling. Furthermore, large vacuoles were noted in basal intraepithelial duct cells. After 2 hours there were ruptures of secretory granule membranes in BG and mitochondrial swelling and degeneration of sustentacular cells. The basal cells were less damaged. After four hours the neuroepithelium was disorganized although the columnar organization of neurons was largely intact. The acinar organization of the BG was frequently lost. The subsequent detachment of the neuroepithelium is suggested to be secondary to extensive damage of BG excretory ducts and sustentacular cells.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Methimazole-Induced Damage in the Olfactory Mucosa: Effects on Ultrastructure and Glutathione Levels

et al. 2003

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“…Styrene treatment caused a significant decrease in GSH to 70.6%, and a significant increase in lipid peroxide to 163.7% of the controls (Fig. 4), consistent with previous findings that styrene inducing oxidative stress occurs in its biotransformation process concomitant with the decrease in GSH levels (14,24). As shown in Fig.…”

Section: Inhibition By Gd Against Oxidative Stressmentioning

confidence: 98%

“…It is considered that the main sources of hepatic ROS generation are P450 enzymes, mitochondria and Kupffer cells, and that the elevated cellular oxygen radicals consequently affect hepatic GSH and lipid peroxide (2,4,14,26). Our results suggested that post-treatment with Gd could contribute to an improvement in the redox status altered by styrene treatment, and eventually would contribute to protection of rat liver from styrene damage through alleviating styrene-inducible P450 expressions such as CYP1A2, CYP2B1/2, and CYP3A2 ( Figs.…”

Section: Inhibition By Gd Against Oxidative Stressmentioning

confidence: 99%

“…They have also been suggested to be involved in the metabolic biotransformation from styrene to SO (16,17). Styrene metabolite "SO" causes oxidative stress in its biotransformation process in the liver and lungs of experimental animals (23), concomitant with alterations of GSH and lipid peroxide levels (14,21), DNA adducts, strand breaks and micronuclei in mice lung (25). Hence biotransformation of styrene to SO plays a crucial role.…”

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Gadolinium chloride suppresses styrene-induced cytochrome P450s expression in rat liver

Hirasawa¹,

Kawagoe²,

Wang³

et al. 2007

Biomed. Res.

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To assess the effect of gadolinium (Gd) on the expression of several forms of cytochrome P450 (P450s) and antioxidant enzymes, we treated rats with gadolinium chloride (25 mg as Gd/kg body weight) 4 h after styrene (a multiple P450 inducer) treatment (600 mg/kg). Gd treatment significantly suppressed styrene-inducible cytochrome P4502B1 (CYP2B1), CYP2B2, CYP2E1, and CYP3A2 mRNA expressions to 48.6%, 69.8%, 61.1%, and 38.5%, accompanying with the reduction of proteins expression to 1.42%, 31.2%, 21.1% and 21.1%, respectively, compared with styrene alone treatment. Gd suppressed styrene-inducible CYP1A2 expression, but only at the protein level. On the other hand, styrene treatment caused a decrease in reduced form of glutathione (GSH), as well as increases in lipid peroxide and serum ALT and AST activities, suggesting the occurrence of hepatic damage probably due to styrene-induced oxidative stress in rat liver. Post-treatment of Gd attenuated this styrene-caused hepatic damage. Moreover, mRNA expressions of cellular antioxidant enzymes such as catalase, CuZn-superoxide dismutase (CuZnSOD) and glutathione peroxidase (GPX) were hardly changed by styrene and/or Gd treatment. In summary, Gd suppressed styrene-inducible expression of not only CYP2B1 but also several forms of P450 at both the mRNA and protein levels, along with attenuation of styrene-caused liver damage. These findings suggested that Gd is a chemo-preventive agent against hepatic damage caused by xenobiotics requiring biotransformation.

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Th2 cytokine‐mediated methimazole‐induced acute liver injury in mice

Kobayashi

Higuchi

Ide³

et al. 2012

J of Applied Toxicology

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Drug-induced liver injury (DILI) is a major safety concern in drug development and clinical practice. The pathogenesis of DILI usually involves the participation of the parent drug or metabolites that either affect cellular function or elicit an immune response. However, the mechanisms leading to DILI are unknown in most cases. Methimazole (MTZ) is used as an antithyroid drug and is well known to have induced liver injuries such as cholestatic hepatitis in a small number of human cases. Immune-mediated reactions were also suggested to play a role in MTZ-induced acute liver injury, but the mechanism underlying this process has not been elucidated. To address this issue, we measured plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, hepatic glutathione levels, hepatic expression of CD4⁺ Th cell-related transcriptional factors, cytokines and chemokines, plasma interleukin (IL)-4 levels and histopathological changes in the liver following MTZ (450 mg kg⁻¹ , p.o.) administration in mice. The hepatic expression of mRNA for Th2 cell-related factors, such as GATA-binding protein, macrophage inflammatory protein-2 (MIP-2) and plasma IL-4 levels, as well as plasma AST and ALT levels, was significantly increased in mice treated with MTZ. These changes were markedly enhanced by pre-treatment with L-buthionine sulfoximine (3 mmol kg⁻¹, i.p.) and MTZ (15 mg kg⁻¹, p.o.). Neutralization of IL-4 using a monoclonal anti-mouse IL-4 antibody (100 µg/mouse, single i.p.) suppressed the hepatotoxic effect of MTZ. In conclusion, this report is the first to demonstrate that Th2 cytokine-mediated immune responses are involved in MTZ-induced acute liver injury in mice.

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Metabolism-dependent hepatotoxicity of methimazole in mice depleted of glutathione

Cited by 43 publications

References 24 publications

Methimazole-Induced Damage in the Olfactory Mucosa: Effects on Ultrastructure and Glutathione Levels

Methimazole-Induced Damage in the Olfactory Mucosa: Effects on Ultrastructure and Glutathione Levels

Gadolinium chloride suppresses styrene-induced cytochrome P450s expression in rat liver

Th2 cytokine‐mediated methimazole‐induced acute liver injury in mice

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