Investigations of the pathways of toxicity of methyl iodide in the rat nasal cavity

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

doi:10.1016/s0300-483x(98)00084-5

Cited by 23 publications

(15 citation statements)

References 43 publications

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“…After 6 h of exposure, GSH levels in the olfactory and respiratory epithelia of the 100-ppm exposed animals were 24% and 14% of control, respectively. These changes are similar to those previously reported for rats exposed to MeI (Chamberlain et al, 1998a;Kirkpatrick, 2002). GSH levels appeared to rebound after cessation of exposure, particularly around the 24-and 48-h collection times, as indicated by percent of control values ranging from 108% to 158%.…”

Section: Parametersupporting

confidence: 91%

“…Animals were subject to whole-body exposure 6 h per day for up to 2 days to either 0, 25, or 100 ppm MeI. The exposure concentrations were selected based on data generated from previous inhalation studies (Chamberlain et al, 1998a;Kirkpatrick, 2002). Time-course experiments were conducted using three rats per exposure concentration per time point and included measurements of serum iodide, and GSH in blood, liver, kidney, and nasal olfactory and respiratory epithelia at 0 (control only) and 1, 3, 6, 9, 24, 27, 30, 33, and 48 (control and exposed) h after initiation of the study.…”

Section: Experimental Designmentioning

confidence: 99%

“…Although the mechanism for the toxicity is not known, it is clear that glutathione (GSH) plays a role (Chamberlain et al, 1998a(Chamberlain et al, , 1998b. In vitro, glutathione conjugates with MeI in nasal tissue to form S-methyl GSH, with the rate being higher in olfactory epithelium than in respiratory epithelium (Chamberlain et al, 1998a). Depletion of nonprotein sulfhydryls (NPSH) occurred in nasal tissue of rats exposed for 6 h to 100 ppm MeI (Chamberlain et al, 1998b).…”

Section: Introductionmentioning

confidence: 99%

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Two-day inhalation toxicity study of methyl iodide in the rat

Himmelstein

Kegelman

DeLorme

et al. 2009

Inhalation Toxicology

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The effects of inhaled methyl iodide (MeI) on clinical pathology parameters, glutathione (GSH) tissue levels, serum thyroid hormone and inorganic iodide concentrations, S-methylcysteine hemoglobin concentrations, and liver UDP-glucuronyltransferase activity were studied in the rat. Male rats were exposed by whole-body inhalation to 0, 25, or 100 ppm MeI, 6 h/day for up to 2 days. Serum cholesterol concentrations (both high-density lipoprotein [HDL] and low-density lipoprotein [LDL] fractions) were increased and triglycerides were decreased at both exposure levels. Serum thyroid-stimulating hormone (TSH) concentrations were increased at 25 and 100 ppm, and serum triiodothyronine (T(3)) and thyroxine (T(4)) concentrations were decreased at 100 ppm. There was no change in either reverse triiodothyronine (rT(3)) or UDP-glucuronyltransferase activity at either exposure level. A dose- and time-dependent reduction in GSH levels in blood, kidney, liver, and nasal tissue was observed, with the greatest reduction in nasal tissue (olfactory and respiratory epithelium). MeI exposure also resulted in a substantial dose- and time-dependent increase in both serum inorganic iodide and red blood cell S-methylcysteine hemoglobin adducts. These results indicate that following inhalation exposure, MeI is rapidly metabolized in blood and tissue of rats, resulting in methylation products and release of inorganic iodide.

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Section: Parametersupporting

confidence: 91%

Section: Experimental Designmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Two-day inhalation toxicity study of methyl iodide in the rat

Himmelstein

Kegelman

DeLorme

et al. 2009

Inhalation Toxicology

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“…Finally, the emergence of iodomethane dehalogenase activity in P450 PMO is noteworthy, as mammalian P450s and soluble MMO do not exhibit it. 40,48 Iodomethane is known to be degraded by a very small subset of methylotrophic species, using enzymes such as corrinoid-dependent methyltransferases. 49 The propane-adapted features of P450 PMO 's active site enable the emergence of a basal activity towards this substrate, thus providing an alternative enzymatic strategy for the degradation of this compound and further expanding the range of known P450 activities.…”

Section: Discussionmentioning

confidence: 99%

Evolutionary History of a Specialized P450 Propane Monooxygenase

Fasan

Meharenna

Snow

et al. 2008

Journal of Molecular Biology

187

236

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SummaryThe evolutionary pressures that shaped the specificity and catalytic efficiency of enzymes can only be speculated. While directed evolution experiments show that new functions can be acquired under positive selection with few mutations, the role of negative selection in eliminating undesired activities and achieving high specificity remains unclear. Here we examine intermediates along the 'lineage' from a naturally-occurring C 12 -C 20 fatty acid hydroxylase (P450 BM3 ) to a laboratory-evolved P450 propane monooxygenase (P450 PMO ) having 20 heme domain substitutions compared to P450 BM3 . Biochemical, crystallographic and computational analyses show that a minimal perturbation of the P450 BM3 fold and substrate binding pocket accompanies a significant broadening of enzyme substrate range and the emergence of propane activity. In contrast, refinement of the enzyme catalytic efficiency for propane oxidation (~9,000-fold increase in k cat /K m ) involves profound reshaping and partitioning of the substrate access pathway. Remodeling of the substrate recognition mechanisms ultimately results in remarkable narrowing of the substrate profile around propane and enables the acquisition of a basal iodomethane dehalogenase activity as yet unknown in natural alkane monooxygenases. A highly destabilizing L188P substitution in a region of the enzyme that undergoes a large conformational change during catalysis plays an important role in adaptation to the gaseous alkane. This work demonstrates that positive selection alone is sufficient to completely re-specialize the cytochrome P450 for function on a non-native substrate.

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“…Bioactivation of IDPN, specifically by nasal cytochrome P450 2E1, appears to be critical in the development of nasal toxicity (11). 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).…”

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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Investigations of the pathways of toxicity of methyl iodide in the rat nasal cavity

Cited by 23 publications

References 43 publications

Two-day inhalation toxicity study of methyl iodide in the rat

Two-day inhalation toxicity study of methyl iodide in the rat

Evolutionary History of a Specialized P450 Propane Monooxygenase

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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