Connecting glutathione with immune responses to occupational methylene diphenyl diisocyanate exposure

Details

• Alternative Title:
  Chem Biol Interact
• Personal Author:
  Wisnewski, Adam V ; Liu, Jian ; Redlich, Carrie A
• Description:
  Methylene diphenyl diisocyanate (MDI) is among the leading chemical causes of occupational asthma world-wide, however, the mechanisms of disease pathogenesis remain unclear. This study tests the hypothesis that glutathione (GSH) reacts with MDI to form quasi-stable conjugates, capable of mediating the formation of MDI-conjugated "self" protein antigens, which may participate in pathogenic inflammatory responses. To test this hypothesis, an occupationally relevant dose of MDI (0.1%w/v) was reacted with varying concentrations of GSH (10μM-10mM), and the reaction products were characterized with regard to mass/structure, and ability to carbamoylate human albumin, a major carrier protein for MDI in vivo. LC-MS/MS analysis of GSH-MDI reaction products identified products possessing the exact mass of previously described S-linked bis(GSH)-MDI and its partial hydrolysis product, as well as novel cyclized GSH-MDI structures. Upon co-incubation of GSH-MDI reaction products with human albumin, MDI was rapidly transferred to specific lysines of albumin, and the protein's native conformation/charge was altered, based on electrophoretic mobility. Three types of modification were observed, intra-molecular MDI cross-linking, addition of partially hydrolyzed MDI, and addition of "MDI-GSH", where MDI's 2nd NCO had reacted with GSH's "N-terminus". Importantly, human albumin carbamoylated by GSH-MDI was specifically recognized by serum IgG from MDI exposed workers, with binding dependent upon the starting GSH concentration, pH, and NaCl levels. Together, the data define a non-enzymatic, thiol-mediated transcarbamoylating mechanism by which GSH may promote immune responses to MDI exposure, and identify specific factors that might further modulate this process.
• Subjects:
  Adult Albumin Albumins Allergens Article Asthma, Occupational Benzhydryl Compounds Carbamoylation Case-Control Studies Exposure Female Glutathione Glutathione (GSH) Humans Isocyanates Male Methylene Diphenyl Diisocyanate (MDI) Middle Aged Occupational Exposure Tandem Mass Spectrometry

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• Source:
  Chem Biol Interact. 2013; 205(1):38-45.
• Pubmed ID:
  23791970
• Pubmed Central ID:
  PMC3767171
• Document Type:
  Journal Article
• Funding:
  2R42ES018021/ES/NIEHS NIH HHS/United States ; OH009762/OH/NIOSH CDC HHS/United States ; R21OH01043/OH/NIOSH CDC HHS/United States ; R42 ES018021/ES/NIEHS NIH HHS/United States
• Volume:
  205
• Issue:
  1
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:7d6ae984d8c369f3d12dfda33edc209891c97be25a0222aa5bce2c72ec12e78f
• Download URL:
  https://stacks.cdc.gov/view/cdc/29726/cdc_29726_DS1.pdf
• File Type:
  [PDF - 601.01 KB ]