Synthesis and spectroscopic characterization of 4-chlorophenyl isocyanate (= 1-chloro-4-isocyanatobenzene) adducts with amino acids as potential dosimeters for the biomonitoring of isocyanate exposure

摘要

Blood-protein adducts are used as dosimeter for modifications of macromolecules in the target organs where the disease develops. The functional groups of cysteine, tyrosine, serine, lysine, tryptophan, histidine and N-terminal amino acids are potential reaction sites for isocyanates. Especially the N-terminal amino acids, valine and aspartic acid of hemoglobin and albumin, respectively, are reactive towards electrophilic xenobiotics. To develop methods for the quantification of such blood-protein adducts, we treated 4-chlorophenyl isocyanate (1) with the tripeptide L-valyl-glycyl-glycine (2a) a nd with single amino acids yielding N-[(4-chlorophenyl)carbamoyl]valyl-glycyl-glycine (3a), N-[(4-chlorophenyl)carbamoyl]valine (3b), N-[(4-chlorophenyl)carbamoyl]aspartic acid (3c), N-[(4-chlorophenyl)carbamoyl]glutamic acid (3d), N-acetyl-S-[(4-chlorophenyl)carbamoyl]cysteine (3e), and N-acetyl-O-[(4-chlorophenyl)carbamoyl]serine (3f), N-alpha-acetyl-N-epsilon-[(4-chlorophenyl)carbamoyl]lysine (3g). For several chemicals, it was shown that blood-protein adducts are good dosimeters of exposure and dosimeters for the target dose. The hydrolysis of the N-terminal adducts of isocyanates release hydantoins which can be separated From the rest of the protein and analyzed using GC/MS or HPLC. This was achieved with 3a. The released hydantoin could be analyzed using GC/MS. We propose to analyze the N-terminal adducts of isocyanates with blood protein to distinguish between arenamine and arylisocyanate exposure. [References: 46]