The role of glutathione S-transferase- and cytochrome P450-dependent metabolism in the olfactory toxicity of methyl iodide in the rat

Chamberlain, M.; Lock, Edward A.; Gaskell, Barbara A.; Reed, Celia J.

doi:10.1007/s002040050522

Cited by 28 publications

(20 citation statements)

References 42 publications

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“…The reason for the increased susceptibility to methimazole in GSH-depleted mice is not known and no further attempts to examine these effects have been made. An increased susceptibility has also been observed following administration of the olfactory toxicant methyl iodide to GSH-depleted animals (8).…”

Section: Discussionmentioning

confidence: 98%

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: Discussionmentioning

confidence: 98%

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

et al. 2003

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“…p-Chloromercuribenzoic acid (PCMB), an anionic probe of moderate size, caused the oocytes to swell and burst at a concentration of 0.2 mM (data not shown). This was attributed to the entry of PCMB into the oocytes by non-ionic diffusion and the subsequent inhibition of energy metabolism, since several steps in glycolysis and oxidative phosphorylation are known to be sensitive to sulphydryl reagents [25][26][27]. By contrast, p-chloromercuribenzosulfonate (PCMBS), a bulky anion believed to be membrane impermeant [14,28], did not cause the oocytes to burst and had little or no effect on wild-type CFTR-mediated Cl -currents, even at concentrations as high as 1.3 mM.…”

Section: +mentioning

confidence: 99%

Intracellular Cysteines of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulate Channel Gating

Ketchum¹,

Yue²,

Alessi³

et al. 2002

Cell Physiol Biochem

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The cystic fibrosis transmembrane conductance regulator (CFTR), a member of the ATP-binding cassette superfamily, is a cAMP-activated chloride channel. CFTR contains two transmembrane domains (TMDs), two nucleotide-binding domains (NBDs), and a regulatory (R) domain. We found that whole-cell CFTR-dependent Cl- currents in Xenopus laevis oocytes were sensitive to HgCl₂, suggesting that modification of endogenous cysteines alters channel activity. To understand better this phenomenon, site-directed mutagenesis was employed to generate both individual cysteine replacements and a version of the molecule with no cysteines in the hydrophobic sector. Each mutant displayed a forskolin/IBMX-activated Cl^- conductance similar to wild type, indicating that none of the cysteines located within the TMDs is essential. Subsequent single-channel analysis of inside-out patches excised from HEK293 cells expressing either cysteine-less or wild-type CFTR showed that intracellular application of a membrane impermeant sulphydryl reagent, p-chloromercuribenzosulfonate (PCMBS), significantly reduced open probability without affecting ion selectivity or conductance. The cysteine-less molecule also acquired a voltage-dependent sensitivity to extracellular PCMBS not observed in the wild type, perhaps due to a more flexible conformation that allowed PCMBS access to the intracellular surface. Together, these experiments suggest that endogenous intracellular cysteines, located primarily within the NBDs and/or R domain, influence channel gating.

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“…Inhalation of methyl iodide (MeI) results in toxicity to many organs including the olfactory epithelium (30), where it undergoes conjugation with glutathione catalysed by glutathione S-transferase T1-1 (6). Although this appears to be a detoxification reaction (7), it has been suggested that the resultant rapid and extensive depletion of intracellular glutathione may make the olfactory epithelium vulnerable to oxidative damage (7). Methyl methacrylate (MMA) is a potent olfactory toxin following inhalation exposure (14,15).…”

Section: Introductionmentioning

confidence: 99%

Three-Dimensional Mapping of the Lesions Induced by β-β'-Iminodiproprionitrile, Methyl Iodide and Methyl Methacrylate in the Rat Nasal Cavity

et al. 2003

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The nasal cavity is an important target organ for toxicity, and many chemicals induce site-specific lesions in this region. The factors responsible for this site-selectivity have not been unequivocally identified, but probably include regional dosimetry and bioactivation. The purpose of this study was to map, in 3 dimensions, the lesions induced by β-β -iminodipropionitrile (IDPN), methyl iodide (MeI) and methyl methacrylate (MMA) in the rat nasal cavity. Animals were administered IDPN (150 mg/kg, IP) or exposed via inhalation to MeI (100 ppm, 2 hours) or MMA (400 ppm, 4 hours) and sacrificed after 24 hours. Heads were decalcified, step-sections (1 every 400 µm) cut and stained, and the severity of the epithelial lesion graded as mild (vacuolation and pyknosis), moderate (undulation and mild stripping), or marked (complete stripping). These grades were mapped onto a 3D-model of a rat nasal cavity using the KS400 imaging system (Imaging Associates, Thame, UK). Despite the different routes of exposure the lesions induced by the 3 compounds had very similar distributions, predominantly affecting the dorsal-medial aspects of the ethmoturbinates and, in the case of MMA, the organ of Rodolfo Masera. These results suggest that, with these chemicals, local bioactivation plays a more important role than dosimetry in determining lesion distribution.

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The role of glutathione S-transferase- and cytochrome P450-dependent metabolism in the olfactory toxicity of methyl iodide in the rat

Cited by 28 publications

References 42 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

Intracellular Cysteines of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulate Channel Gating

Three-Dimensional Mapping of the Lesions Induced by β-β'-Iminodiproprionitrile, Methyl Iodide and Methyl Methacrylate in the Rat Nasal Cavity

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