Thiols and disulphides can aggravate peroxynitrite-dependent inactivation of alpha1-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 alpha1-antiproteinase (alpha1AP), 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 alpha1AP 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 alpha1AP. This must be considered in attempts to use thiols as 'peroxynitrite scavengers'.