Copper‐catalyzed thermal aggregation of human gamma‐globulin inhibition by histidine, gold thiomalate, and penicillamine

Abstract

Gold thiomalate (40 pM), penicillamine (40 pM), and histidine (20 pM) inhibit the copper-catalyzed (20 pM) thermal aggregation of human gamma globulin (0.8 mg/ml). At these concentrations, inhibition of gamma globulin aggregation was 87%, 96%, and 99% complete. This effect may be related to the reported suppressive effect of these agents in rheumatoid arthritis and adds support to the hypothesis that the hypohistidinemia of rheumatoid arthritis participates in the pathogenesis of the disease. Gold thiomalate (l), D-penicillamine (2),and L-histidine (3,4) have been reported to be effective in the treatment of rheumatoid arthritis. There is good evidence that aggregated gamma globulin is inflammatory, antigenic, and a stimulus to the formation of rheumatoid factors (5). There is also some evidence for the presence of aggregated gamma globulin in the synovial fluid of patients with rheumatoid arthritis (6,7).

Low free serum histidine concentration in rheumatoid arthritis. A measure of disease activity.

“…It has been proposed that hypohistidinemia, because of an associated low synovial fluid histidine concentration (26), contributes to the pathogenesis of rheumatoid arthritis by permitting the sulfhydryl-dependent hyaluronate-augmented aggregation of synovial fluid gamma globulin, generating in the joint fluid an inflammatory and antigenic substance (aggregated gamma globulin) (27,28). The observations in the present study are consistent with this hypothesis.…”

Inhibition of human endothelial cell proliferation by gold compounds.

“…Suggested mechanisms underlying the therapeutic efficacy ofthese drugs include the inhibition oflysosomal or other cellular enzymes (26)(27)(28), interference with complement activation (29,30), inhibition ofprostaglandin biosynthesis (31,32), alterations in protein interactions (33)(34)(35)(36) and sulfhydryl reactivity (37), and nonspecific antiinflammatory activity (38). It has also been suggested that they block the accessory cell functions of macrophages, leading to regression of cell-mediated immunological reactions (39).…”

Effect of one gold salt, of betamethasone, and of aspirin on the chemotaxis of human neutrophils measured in vitro.

“…Aggregated immunoglobulin was also the substance chosen in our experiments for generating chemotactic activity in plasma. Gerber (1971) has reported that gold thiomalate inhibited the heat aggregation of human gammaglobulin. In our experiments the gold salt was added to the plasma at the same time as the aggregated gammaglobulin and not during the gammaglobulin heating phase.…”