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'.
Whiteman
M
M
Neurodegenerative Disease Research Centre, King's College London, UK.
Halliwell
B
B
D004220:Disulfides / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006997:Hypochlorous Acid / Q000494:pharmacology; D009566:Nitrates / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000494:pharmacology*; D014443:Tyrosine / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000187:drug effects* / Q000378:metabolism*
D004220:Disulfides; D009566:Nitrates; D013438:Sulfhydryl Compounds; D000515:alpha 1-Antitrypsin; C039642:peroxynitric acid; D014443:Tyrosine; D006997:Hypochlorous Acid