Effect of auranofin and other gold complexes on the activity of phospholipase C.

Auranofin (AF) is an orally active chrysotherapeutic agent used for the treatment of rheumatoid arthritis, a self-perpetuating inflammatory disease. Because of reports suggesting that AF and other gold complexes can, under certain circumstances, exacerbate rheumatoid inflammatory lesions in humans and adjuvant arthritic rats and that phospholipase C (PLC) and phospholipase A2 activities are increased in rheumatoid patients, the effects of AF and a related gold complex on in situ mammalian and purified Bacillus cereus PLC were examined. Results of our studies show that 1) AF and triethylphosphine gold chloride (TEPG), an AF analog, stimulated PLC activity in the sonicate of RAW 264.7 macrophages; 2) AF and TEPG stimulated B. cereus PLC activity in a concentration-dependent manner, but the pattern of stimulation and concentrations of drugs required to stimulate the purified enzyme differ from those seen with the macrophage PLC; 3) metals (cobalt and zinc) and sulfhydryl reagents (N-ethylmaleimide, iodoacetic acid, and glutathione), tested at the same concentrations of AF that enhanced PLC activity, had no effect on the enzyme. These data suggest that stimulation of PLC may be a generic phenomenon since two divergent PLCs are affected by gold complexes. Additionally, these studies may provide one potential explanation for rheumatoid lesion flares seen in patients and animals on chrysotherapy.