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 understa nd the mechanism of production of aurocyanide, we investigated the inv olvement of myeloperoxidase in the reaction. This haem enzyme of neutr ophils and monocytes uses hydrogen peroxide to oxidise chloride and th iocyanate to hypochlorous acid and hypothiocyanite, respectively. When aurothiomalate (10 mu M) was incubated with thiocyanate (200 mu M), h ydrogen peroxide (100 mu M) and myeloperoxidase (20 nM), it was transf ormed to a product that was spectrally identical to authentic aurocyan ide. Aurothiomalate was quantitatively converted to aurocyanide in abo ut 10 min at pH 6.0 and in 40 min at pH 7.4. Aurocyanide formation occ urred after myeloperoxidase had used all the hydrogen peroxide availab le to produce hypothiocyanite. Thus, the cyanide must have formed from the slow decomposition of hypothiocyanite. The rate of aurocyanide pr oduction was increased in the presence of 100 mM chloride, which indic ates that hypochlorous acid accelerates the formation of cyanide. Hypo chlorous acid (100 to 400 mu M) reacted non enzymatically with thiocya nate (200 mu M) and aurothiomalate (10 mu M) to produce aurocyanide. T hus, aurocyanide is produced by two processes, involving both the form ation of hypothiocyanite and hypochlorous acid. Aurocyanide is an effe ctive inhibitor of the respiratory burst of neutrophils and monocytes and the proliferation of lymphocytes. Therefore, aurothiomalate may at tenuate inflammation by acting as a pro-drug which is reliant on neutr ophils and monocytes to produce hypothiocyanite. When the hypothiocyan ite decays to hydrogen cyanide, the pro-drug is converted to aurocyani de which then suppresses further oxidant production by these inflammat ory cells. BIOCHEM I PHARMACOL 56;3:307-312, 1998. (C) 1998 Elsevier S cience Inc.