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.