It is assumed that effects of the thiol antioxidant N-acetylcysteine are mediated by interaction with protein-associated cysteine residues, however, information on protein level in vivo are missing. Therefore, we analyzed N-acetylcysteine-induced modifications of the protein transthyretin (TTR) in plasma of hemodialysis patients in a randomized, placebo-controlled study. TTR was selected due to its low molecular weight and the free cysteine residue in the polypeptide chain, which is known to be extensively modified by formation of mixed disulfides. The intravenous application of N-acetylcysteine during a hemodialysis session resulted in a substantial increase of native TTR from median 15% (range 8.8-30%) to median 40% (37-50) and reduction of S-cysteinylated TTR [51% (44-60) vs. 6.6% (2.4-10)]. Additionally the pronounced formation of a TTR-N-acetylcysteine adduct was detected. However, all these modifications seemed to be reversible. Additionally, in vitro incubation of plasma with N-acetylcysteine confirmed the in vivo results and indicated that changes in PTM pattern of TTR were a function of N-acetylcysteine concentration. Based on these observations and the essential metabolic and biochemical role of protein-associated cysteine residues we hypothesize that the interaction of N-acetylcysteine with proteins may explain altered protein functions due to modification of cysteine residues.
Antioxidants and Redox Signaling, 2013, Vol 19, Issue 11, p. 1166-1172