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

Details

• Personal Author:
  Hettick JM ; Siegel, Paul D. ; Wisnewski AV
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Biochemistry Hazardous Substances Immune System Laboratories Occupational Health Safety
• Keywords:
  Biochemical-analysis Biohazards Biological-effects Cellular-reactions Immune-reaction Immune-system Immunochemistry Laboratory-testing
• ISSN:
  0893-228X
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  Connecticut ; OSHA Region 1 ; OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  24
• Issue:
  10
• NIOSHTIC Number:
  nn:20039913
• Citation:
  Chem Res Toxicol 2011 Oct; 24(10):1686-1693
• Contact Point Address:
  Adam V. Wisnewski, Yale School of Medicine, 300 Cedar Street, TAC-S4157, P.O. Box 208057, New Haven, CT 06520-8057
• Email:
  adam.wisnewski@yale.edu
• CAS Registry Number:
  Toluene 2,4-diisocyanate (CAS RN 584-84-9)
• Federal Fiscal Year:
  2012
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  True
• Source Full Name:
  Chemical Research in Toxicology
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:36ae7485745a950e5b245a2abe85d5aa7fdc5d38c1a72abbd8ec0d6757bdafa9b6bc184cfad137abf9db7cbac56c157dca437c38b2933c7dc13894e074352a08
• Download URL:
  https://stacks.cdc.gov/view/cdc/192966/cdc_192966_DS1.pdf
• File Type:
  [PDF - 3.51 MB ]