Effects of formaldehyde inhalation on the junctional proteins of nasal respiratory mucosa of rats

Arican, Ramazan Yavuz; Sahin, Zeliha; Üstünel, İ̇smail; Sarıkcıoğlu, Levent; Özdem, Sebahat; Oğuz, Nurettin

doi:10.1016/j.etp.2008.09.005

Cited by 16 publications

(13 citation statements)

References 24 publications

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“…E-cad interacts with many other proteins in the junctional complex, including the claudins and occludins, and is able to increase the strength and stability of the complex via catenin-modulated binding to the actin cytoskeleton [van Roy et al, 2008]. E-cad is critical to the maintenance of mucosal integrity and has been shown to play a defensive role in response to nasal [Arican et al, 2009] and laryngeal [Gill et al, 2005;Sivasankar et al, 2010] mucosal challenges. In this study, we identified strong E-cad immunoactivity in cells along the luminal surface of the newly reconstructed epithelium postinjury.…”

Section: Discussionmentioning

confidence: 99%

E-Cadherin and Transglutaminase-1 Epithelial Barrier Restoration Precedes Type IV Collagen Basement Membrane Reconstruction following Vocal Fold Mucosal Injury

Ling

Raasch

Welham

2010

Cells Tissues Organs

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The vocal fold epithelium is critical to upper airway immunologic defense and water/ion transport; therefore, any form of physical trauma or insult increases the vulnerability of this structure to functional impairment and pathogen invasion/infection. In this study, we examined the reestablishment of epithelial and basement membrane barrier structures in a well-established rat model of vocal fold mucosal injury. We observed active cell recruitment culminating in peak hyperplasia at 3 days postinjury, the establishment of robust E-cadherin+ and transglutaminase-1+ biochemical barrier signals along the epithelial surface by 3 days postinjury, and the persistent absence of a type IV collagen+ basement membrane at 7 days postinjury. The distinct spatial and temporal immunoactivity of these molecules is consistent with a programmed repair process driving the restoration of vocal fold mucosal integrity and permeability. These data may inform future efforts to optimize functional mucosal recovery postinjury and avoid undesirable events such as barrier compromise or epithelial metaplasia.

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Section: Discussionmentioning

confidence: 99%

E-Cadherin and Transglutaminase-1 Epithelial Barrier Restoration Precedes Type IV Collagen Basement Membrane Reconstruction following Vocal Fold Mucosal Injury

Ling

Raasch

Welham

2010

Cells Tissues Organs

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“…Prolonged exposure of rats to high concentrations of inhaled formaldehyde has been shown to significantly decrease the density of structural proteins of the junctional complex in the nasoepithelium. 109 On the other hand, a number of highly effective detoxification reactions based mainly on aldehyde dehydrogenase activity and glutathione conjugation (for unsaturated aldehydes) are capable of offsetting potential toxic effects to a greater or lesser extent, depending on the particular biological system. 110 Thus, aldehyde toxicology is characterized by the presence of thresholds, marked differences between in Vitro and in ViVo evaluations and differential effects depending on the route of administration.…”

Section: Approaches To Qualification and Specification Setting For Gimentioning

confidence: 99%

Genotoxic Impurities: From Structural Alerts to Qualification

Snodin¹

2010

Org. Process Res. Dev.

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The presence of an in cerebro structural alert in a potential or actual impurity, most likely arising as a byproduct or carriedover reagent or starting material, in a drug substance or drug product is merely an indication that the compound may be a DNAreactive genotoxin. The correlation between structural alerts for direct or indirect electrophilic characteristics and relevant biological activity is highly imperfect. For virtually all actual or potential impurities that are structurally alerting there is likely to be a variety of possibilities for clarifying their genotoxicity status based on published data, in silico assessments or de noWo testing in bacterial reverse mutation assays. Even for compounds that test positive a number of options are available to enable a compoundspecific qualification to be made involving the use of pre-existing toxicological data (particularly from lifetime rodent bioassays) and/ or using information from appropriate additional studies. A review of representative compounds from several classes of structurally alerting substances (epoxides, hydrazines, aromatic amines, halides and aldehydes) provides examples of different types of qualification strategies Overall, it seems prudent to obtain maximum "leverage" from toxicological approaches, which are likely to be relatively low cost, before making any significant process-related changes to an active pharmaceutical ingredient (API) synthesis.

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“…The band was electrophoresed for 1 h in 150 V to recovery the protein [27] . After the second electrophoresis, 50 µL of running buffer solution containing [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]houttuyninmodified HSA in dialysis tubing was dissolved in 500 μL scintillation fluid, and the radioactivity was compared with the control sample by liquid scintillation counting.…”

Section: Animals and Treatmentmentioning

confidence: 99%

“…It has been reported that some aldehyde compounds, such as formaldehyde [12,13] , acetaldehyde [14,15] , acrolein [16,17] , 2-nonenal [18,19] , and aldehyde intermediates formed by metabolism [20][21][22] [23] . Therefore, we hypothesized that the acute or idiosyncratic toxicities of houttuyniae injection might be caused by the covalent binding of β-keto aldehyde compounds to cellular proteins.…”

Section: Introductionmentioning

confidence: 99%

Covalent protein binding and tissue distribution of houttuynin in rats after intravenous administration of sodium houttuyfonate

Deng

Zhong

et al. 2012

Acta Pharmacol Sin

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Aim: To investigate the potential of houttuynin to covalently bind to proteins in vitro and in vivo and to identify the adduct structures. Methods: Male Sprague-Dawley rats were intravenously injected with sodium houttuyfonate (10 mg/kg). The concentrations of houttuynin in blood, plasma and five tissues tested were determined using an LC/MS/MS method. The covalent binding values of houttuynin with hemoglobin, plasma and tissue proteins were measured in rats after intravenous injection of [1-14 C]sodium houttuyfonate (10 mg/kg, 150 mCi/kg). Human serum albumin was used as model protein to identify the modification site(s) and structure(s) through enzymatic digestion and LC/MS n analysis. Results: The drug was widely distributed 10 min after intravenous injection. The lungs were the preferred site for disposition, followed by the heart and kidneys with significantly higher concentrations than that in the plasma. The extent of covalent binding was correlated with the respective concentrations in the tissues, ranging from 1137 nmol/g protein in lung to 266 nmol/g protein in liver. Houttuynin reacted primarily with arginine residues in human serum albumin to form a pyrimidine adduct at 1:1 molar ratio. The same adduct was detected in rat lungs digested by pronase E. Conclusion: This study showed that the β-keto aldehyde moiety in houttuynin is strongly electrophilic and readily confers covalent binding to tissue proteins, especially lung proteins, by a Schiff's base mechanism. The findings explain partially the idiosyncratic reactions of houttuyniae injection in clinical use.

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Effects of formaldehyde inhalation on the junctional proteins of nasal respiratory mucosa of rats

Cited by 16 publications

References 24 publications

E-Cadherin and Transglutaminase-1 Epithelial Barrier Restoration Precedes Type IV Collagen Basement Membrane Reconstruction following Vocal Fold Mucosal Injury

E-Cadherin and Transglutaminase-1 Epithelial Barrier Restoration Precedes Type IV Collagen Basement Membrane Reconstruction following Vocal Fold Mucosal Injury

Genotoxic Impurities: From Structural Alerts to Qualification

Covalent protein binding and tissue distribution of houttuynin in rats after intravenous administration of sodium houttuyfonate

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