264285-83-8Relevant academic research and scientific papers
Synthetic approaches to obtain amino acid adducts of 4,4′- methylenediphenyl diisocyanate
Sabbioni, Gabriele,Dongari, Nagaraju,Schneider, Siegfried,Kumar, Anoop
, p. 2704 - 2714 (2013/02/23)
4,4′-Methylenediphenyl diisocyanate (MDI) is the most important isocyanate used in the chemical industry. Lung sensitization and asthma are the main types of damage after exposure to MDI. Albumin adducts of MDI might be involved in the etiology of sensitization reactions. It is therefore necessary to have sensitive and specific biomarkers such as blood protein adducts to monitor people exposed to isocyanates. For the discovery of new isocyanate adducts with blood proteins present in vivo, new synthetic standards are needed. To achieve this, we developed five methods to obtain amino acid adducts of MDI. We synthesized and isolated MDI adducts of aspartic acid, glutamic acid, cysteine, and valine. The new adducts were characterized by LC-MS/MS and NMR. We synthesized the corresponding isotope-labeled MDI adducts to develop analytical methods using LC-MS/MS. Glutathione adducts of isocyanates are an important way of transportation of the reactive isocyanates to distant sites from the original site of exposure. Therefore, we used N-acetyl-cysteine adducts of MDI as reactants: N-acetyl-S-[[4-(4-aminobenzyl)phenyl]carbamoyl]-cysteine (MDI-AcCys) and N-acetyl-S-[[4-(4-acetylaminobenzyl)phenyl]carbamoyl]-cysteine (AcMDI-AcCys). MDI-AcCys or AcMDI-AcCys formed adducts with albumin, N α-acetyl lysine, and valine. Isotope-labeled albumin adducts (= d4-MDI-albumin) were synthesized from d4-MDI-AcCys and albumin. d4-MDI-albumin can be used as an internal standard to analyze biological samples. Such an internal standard will not correct only for the extraction recovery of the adducts but also for the potential variation of the enzymatic digestions used in the procedure to analyze albumin adducts of MDI. The synthetic procedures described in this manuscript will be applicable to the synthesis of amino acid adducts from other isocyanates.
Isocyanate-specific hemoglobin adduct in rats exposed to 4,4'- methylenediphenyl diisocyanate
Sabbioni, Gabriele,Hartley, Renate,Henschler, Dietrich,Hoellrigl-Rosta, Andreas,Koeber, Robert,Schneider, Siegfried
, p. 82 - 89 (2007/10/03)
4,4'-Methylenediphenyl diisocyanate (MDI) is the most important of the isocyanates used as intermediates in the chemical industry. Among the main types of damage after exposure to low levels of MDI are lung sensitization and asthma. Protein adducts of MDI might be involved in the etiology of sensitization reactions. It is therefore necessary to have sensitive and specific methods for monitoring the isocyanate exposure of workers. To date, urine metabolites or protein adducts have been used as biomarkers in workers exposed to MDI. However, with these methods it is not possible to determine if the biomarkers result from exposure to MDI or to the parent aromatic amine 4,4'-methylenedianiline (MDA). This work presents a procedure for quantitating isocyanate-specific hemoglobin adducts. Blood proteins are used as markers of exposure and possibly as markers of dose size for the modifications of macromolecules in the target organs where the disease develops. For the quantitation of hemoglobin adducts, N1-[4-(4- isocyanatobenzyl)phenyl]acetamide (AcMDI) was reacted with the tripeptide valylglycyl-glycine and with valine yielding N-[4-(4- acetylaminobenzyl)phenyl]carbamoyl]valylglycyl-glycine and N-[4-[4- (acetylaminobenzyl)phenyl]carbamoyl]valine, respectively. N-[4-[4- (Acetylamino-3,5-dideuteriobenzyl)-2,6-dideuteriophenyl]carbamoyl]valine was synthesized from valine, as was N1-[4-(4-isocyanato-3,5-dideuteriobenzyl)- 2,6-dideuteriophenyl] acetamide, for use as an internal standard. These adducts were cleaved in 2 M HCl to yield the corresponding hydantoins, 3-[4- (4-aminobenzyl)phenyl]-5-isopropyl-1,3-imidazoline-2,4-dione (MDA-Val-Hyd) and 3-[4-(4-amino-3,5-dideuteriobenzyl)-2,6-dideuteriophenyl]-5-isopropyl- 1,3-imidazoline-2,4-dione, respectively. In globin of rats exposed to MDI, MDA-Val-Hyd could be found in a dose-dependent manner. The adduct was identified by HPLC/MS/MS and quantified by GC/MS after derivatization with heptafluorobutyric anhydride. The amount of MDA-Val-Hyd found after acid hydrolysis of globin at 100 °C is about 12 times larger than the sum of N- acetyl-4,4'-methylenedianiline (AcMDA) and MDA obtained from mild base hydrolysis of hemoglobin. The MDA-Val-Hyd is an isocyanate-specific adduct. MDA and AcMDA released after mild base hydrolyses result most likely from a sulfinamide adduct which is a typical adduct of arylamines. According to these results, higher amounts of isocyanate adducts than arylamine adducts should be expected in workers exposed to isocyanates.
