Thiols and disulphides can aggravate peroxynitrite‐dependent inactivation of α₁‐antiproteinase

Peroxynitrite (ONOO − ) is a cytotoxic species formed in vivo. There is considerable interest in the development of ONOO − `scavengers' as therapeutic agents; several thiols have been suggested to fulfil this role. One protein inactivated by ONOO − is α 1 ‐antiproteinase (α 1 AP), the major inhibitor of serine proteinases in human body fluids. At low thiol:ONOO − concentration ratios, several thiols (captopril, penicillamine, cysteine, cystine and penicillamine disulphide) aggravated inactivation of α 1 AP by ONOO − , whereas GSH, GSSG, homocysteine, ergothioneine, N ‐acetylcysteine, lipoate and dihydrolipoate did not. We suggest that sulphur‐containing radicals are produced by reaction of certain thiols/disulphides with ONOO − or ONOO − ‐derived products and could mediate biological damage, including inactivation of α 1 AP. This must be considered in attempts to use thiols as `peroxynitrite scavengers'.