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Hexamethylene diisocyanate (HDI) vapor reactivity with glutathione and subsequent transfer to human albumin.

Authors
Wisnewski-AV; Mhike-M; Hettick-JM; Liu-J; Siegel-PD
Source
Toxicol In Vitro 2013 Mar; 27(2):662-671
NIOSHTIC No.
20042036
Abstract
Introduction: Airway fluid glutathione (GSH) reactivity with inhaled vapors of diisocyanate, a common occupational allergen, is postulated to be a key step in exposure-induced asthma pathogenesis. Methods: A mixed (vapor/liquid) phase exposure system was used to model the in vivo reactivity of inhaled HDI vapor with GSH in the airway fluid. HDI-GSH reaction products, and their capacity to transfer HDI to human albumin, were characterized through mass spectrometry and serologic assays, using HDIspecific polyclonal rabbit serum. Results: HDI vapor exposure of 10 mM GSH solutions resulted in primarily S-linked, bis(GSH)-HDI reaction products. In contrast, lower GSH concentrations (100 lM) resulted in mainly mono(GSH)-HDI conjugates, with varying degrees of HDI hydrolysis, dimerization and/or intra-molecular cyclization, depending upon the presence/absence of H2PO4-/HPO42- and Na+/CI- ions. The ion composition and GSH concentration of the fluid phase, during HDI vapor exposure, strongly influenced the transfer of HDI from GSH to albumin, as did the pH and duration of the carbamoylating reaction. When carbamoylation was performed overnight at pH 7, 25 of albumin's lysines were identified as potential sites of conjugation with partially hydrolyzed HDI. When carbamoylation was performed at pH 9, more rapid (within 3 h) and extensive modification was observed, including additional lysine sites, intra-molecular crosslinkage with HDI, and novel HDI-GSH conjugation. Conclusions: The data define potential mechanisms by which the levels of GSH, H2PO4 -/HPO42-, and/or other ions (e.g. H+/OH-, Na+, Cl-) affect the reactivity of HDI vapor with self-molecules in solution (e.g. airway fluid), and thus, might influence the clinical response to HDI respiratory tract exposure.
Keywords
Vapors; Inhalants; Allergens; Exposure-levels; Pathogenesis; Models; In-vivo-studies; In-vivo-study; Serological-techniques; Serology; Animals; Laboratory-animals; Aerosols; Author Keywords: Hexamethylene diisocyanate (HDI); Vapor; Aliphatic; Albumin; Carbamoylation; Glutathione (GSH)
Contact
Adam V. Wisnewski, Yale School of Medicine, 300 Cedar Street, TACS4157, P.O. Box 208057, New Haven, CT 06520 8057
CODEN
TIVIEQ
CAS No.
822-06-0; 70-18-8
Publication Date
20130301
Document Type
Journal Article
Email Address
adam.wisnewski@yale.edu
Fiscal Year
2013
NTIS Accession No.
NTIS Price
Identifying No.
B20130124
Issue of Publication
2
ISSN
0887-2333
NIOSH Division
HELD
Priority Area
Manufacturing
Source Name
Toxicology in Vitro
State
CT; WV
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