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Toluene diisocyanate reactivity with glutathione across a vapor/liquid interface and subsequent transcarbamoylation of human albumin.

Authors
Wisnewski-AV; Hettick-JM; Siegel-PD
Source
Chem Res Toxicol 2011 Oct; 24(10):1686-1693
NIOSHTIC No.
20039913
Abstract
Glutathione has previously been identified as a reaction target for toluene diisocyanate (TDI) in vitro and in vivo, and has been suggested to contribute to toxic and allergic reactions to exposure. In this study, the reactivity of reduced glutathione (GSH) with TDI in vitro was further investigated using a mixed phase (vapor/liquid) exposure system to model the in vivo biophysics of exposure in the lower respiratory tract. HPLC/MS/MS was used to characterize the observed reaction products. Under the conditions tested, the major reaction products between TDI vapor and GSH were S-linked bis(GSH)-TDI and to a lesser extent mono(GSH)-TDI conjugates (with one N-C-O hydrolyzed). The vapor-phase-generated GSH-TDI conjugates were capable of transcarbamoylating human albumin in a pH-dependent manner, resulting in changes in the self-protein's conformation/charge, on the basis of electrophoretic mobility under native conditions. Specific sites of human albumin-TDI conjugation, mediated by GSH-TDI, were identified (Lys73, Lys159, Lys190, Lys199, Lys212, Lys351, Lys136/137, Lys413/414, and Lys524/525) along with overlap with those susceptible to direct conjugation by TDI. Together, the data extend the proof-of-principle for GSH to act as a "shuttle" for a reactive form of TDI, which could contribute to clinical responses to exposure.
Keywords
Biochemical-analysis; Biochemistry; Biohazards; Biological-effects; Cellular-reactions; Immune-reaction; Immune-system; Immunochemistry; Laboratory-testing
Contact
Adam V. Wisnewski, Yale School of Medicine, 300 Cedar Street, TAC-S4157, P.O. Box 208057, New Haven, CT 06520-8057
CODEN
CRTOEC
CAS No.
584-84-9
Publication Date
20111017
Document Type
Journal Article
Email Address
adam.wisnewski@yale.edu
Fiscal Year
2012
NTIS Accession No.
NTIS Price
Identifying No.
B11232011
Issue of Publication
10
ISSN
0893-228X
NIOSH Division
HELD
Priority Area
Manufacturing
Source Name
Chemical Research in Toxicology
State
WV; CT
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