Effects of antirheumatic drugs on protein sulphydryl reactivity of human serum

Abstract

The effect of a number of antirheumatic drugs on sulphydryl group reactivity in human serum has been determined using the thiol reagent, 5,5′-dithiobis (2-nitrobenzoic acid) (DTNB). Drug effects in vivo have been measured using sera from patients with rheumatoid arthritis receiving these compounds and the drugs have also been added to healthy human serum in vitro. An increased rate of sulphydryl-disulphide exchange between serum sulphydryl groups and DTNB was noted in rheumatoid disease. This finding was not associated with anti-inflammatory drug therapy. In vivo, non-steroidal anti-inflammatory drugs did not affect this reaction, but aurothiomalate, D-penicillamine and levamisole all significantly increased the rate of sulphydryl-disulphide exchange. When the drugs were added to healthy human serum in vitro, indomethacin, aurothiomalate and D-penicillamine stimulated sulphydryl reactivity with DTNB but levamisole had no effect. Aurothiomalate appeared to act in this system as a mixture of gold atoms and thiomalate molecules, the thiomalate stimulating and the gold inhibiting thiol reactivity. This study demonstrates that the stimulation of sulphydryl-disulphide exchange reactions in vivo is a property of three long-acting drugs used to treat rheumatoid arthritis, but not of non-steroidal antiinflammatory agents. This reactivity may therefore differentiate the second-line drugs showing true antirheumatic activity from ‘simple’ anti-inflammatory compounds. Comparative studies have shown that the addition of drugs to serum in vitro may give different results from those obtained with sera from rheumatoid patients receiving these agents. This may be due to in vivo metabolism of the compound, drug concentration effects or the parameters of the in vitro assay system. In view of this, caution is required in the interpretation of data obtained from in vitro studies of these compounds.