The activation of gold complexes by cyanide produced by polymorphonuclear leukocytes. III. The formation of aurocyanide by myeloperoxidase.
There is considerable evidence that the anti-rheumatic gold complexes are activated by their conversion to aurocyanide. In order to understand the mechanism of production of aurocyanide, we investigated the involvement of myeloperoxidase in the reaction. This haem enzyme of neutrophils and monocytes uses hydrogen peroxide to oxidise chloride and thiocyanate to hypochlorous acid and hypothiocyanite, respectively. When aurothiomalate (10 microM) was incubated with thiocyanate (200 microM), hydrogen peroxide (100 microM) and myeloperoxidase (20 nM), it was transformed to a product that was spectrally identical to authentic aurocyanide. Aurothiomalate was quantitatively converted to aurocyanide in about 10 min at pH 6.0 and in 40 min at pH 7.4. Aurocyanide formation occurred after myeloperoxidase had used all the hydrogen peroxide available to produce hypothiocyanite. Thus, the cyanide must have formed from the slow decomposition of hypothiocyanite. The rate of aurocyanide production was increased in the presence of 100 mM chloride, which indicates that hypochlorous acid accelerates the formation of cyanide. Hypochlorous acid (100 to 400 microM) reacted non-enzymatically with thiocyanate (200 microM) and aurothiomalate (10 microM) to produce aurocyanide. Thus, aurocyanide is produced by two processes, involving both the formation of hypothiocyanite and hypochlorous acid. Aurocyanide is an effective inhibitor of the respiratory burst of neutrophils and monocytes and the proliferation of lymphocytes. Therefore, aurothiomalate may attenuate inflammation by acting as a pro-drug which is reliant on neutrophils and monocytes to produce hypothiocyanite. When the hypothiocyanite decays to hydrogen cyanide, the pro-drug is converted to aurocyanide which then suppresses further oxidant production by these inflammatory cells.
Graham
G G
GG
Department of Pathology, Christchurch School of Medicine, New Zealand. g.graham@unsw.edu.au
Kettle
A J
AJ
D018501:Antirheumatic Agents / Q000378:metabolism*; D002712:Chlorides / Q000494:pharmacology; D003485:Cyanates; D003486:Cyanides / Q000378:metabolism*; D006046:Gold; D017612:Gold Compounds / Q000378:metabolism*; D006052:Gold Sodium Thiomalate / Q000378:metabolism*; D006801:Humans; D009504:Neutrophils / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism*
D018501:Antirheumatic Agents; D002712:Chlorides; D003485:Cyanates; D003486:Cyanides; D017612:Gold Compounds; C043041:gold cyanide; D006052:Gold Sodium Thiomalate; D006046:Gold; D009195:Peroxidase