Abstract
Leads to the cellular effects of the anti-arthritic gold complexes may come from
the determination of their metabolism by target cells and, possibly, cells in the immediate
environment of the target cells. Polymorphonuclear leukocytes (PMN) and mononuclear cells
(monocytes and lymphocytes) are present in inflamed joints of patients with rheumatoid arthritis and
these cells have been widely used in pharmacological studies on the gold complexes. It is
suggested that the cellular effects of the gold complexes are mediated by the production of
aurocyanide. According to this hypothesis, PMN metabolize small quantities of thiocyanate to
cyanide which, in turn, converts gold complexes, such as aurothiomalate, to aurocyanide
(dicyanogold(I)) which inhibits the functions of PMN and other cells. There is now considerable
evidence for this hypothesis from in vitro studies but there is little in vivo work to back up the
hypothesis. One of the few in vivo studies which tested the hypothesis involved the examination
of the activity of aurothiomalate in the treatment of polyarthritis in Hooded Wistar rats. Activity of
aurothiomalate is only shown in animals which received thiocyanate. Hydrogen cyanide is a
constituent of cigarette smoke and the aurocyanide formed by the interaction with gold complexes
and inhaled hydrogen cyanide rapidly diffuses into red blood cells. Because of the metabolism of
hydrogen cyanide to thiocyanate in the liver, there are higher plasma levels of thiocyanate in
smokers than in non-smokers. Smokers may have a greater incidence of side effects than non-smokers
but there appears to be little difference in therapeutic response, possibly because there is
sufficient thiocyanate in extracellular fluid, even in non-smokers, to support the conversion of gold
complexes to aurocyanide. The relationship between the metabolism and effects of the orally
active gold complex, auranofin are less clear. Auranofin itself is taken up by cells with the loss of the
ligands bound to gold while its inhibitory activity against the oxidative burst of PMN decreases with
increasing cell density. For example, the lucigenin-dependent chemiluminescence of