Cuperus R A, Hoogland H, Wever R, Muijsers A O
Biochim Biophys Acta. 1987 Mar 18;912(1):124-31. doi: 10.1016/0167-4838(87)90255-x.
The inhibitory effect of the anti-arthritic drug D-penicillamine on the formation of hypochlorite (HOCl) by myeloperoxidase from H2O2 and Cl- was investigated. When D-penicillamine was added to myeloperoxidase under turnover conditions, Compound III was formed, the superoxide derivative of the enzyme. Compound III was not formed when D-penicillamine was added in the presence of EDTA or in the absence of oxygen. However, when H2O2 was added to myeloperoxidase, D-penicillamine and EDTA, Compound III was formed. Therefore it is concluded that formation of Compound III is initiated by metal-catalysed oxidation of the thiol group of this anti-arthritic drug, resulting in formation of superoxide anions. Once Compound III is formed, a chain reaction is started via which the thiol groups of other D-penicillamine molecules are oxidized to disulphides. Concomitantly, Compound I of myeloperoxidase would be reduced to Compound II and superoxide anions would be generated from oxygen. This conclusion is supported by experiments which showed that formation of Compound III of myeloperoxidase by D-penicillamine depended on the chloride concentration. Thus, an enzyme intermediate which is active in chlorination (i.e. Compound I) participated in the generation of superoxide anions from the anti-arthritic drug. From the results described in this paper it is proposed that D-penicillamine may exert its therapeutic effect in the treatment of rheumatoid arthritis by scavenging HOCl and by converting myeloperoxidase to Compound III, which is inactive in the formation of HOCl.
研究了抗关节炎药物D-青霉胺对髓过氧化物酶利用H2O2和Cl-生成次氯酸盐（HOCl）的抑制作用。在周转条件下，当向髓过氧化物酶中加入D-青霉胺时，会形成化合物III，即该酶的超氧化物衍生物。在EDTA存在下或无氧条件下加入D-青霉胺时，不会形成化合物III。然而，当向髓过氧化物酶、D-青霉胺和EDTA中加入H2O2时，会形成化合物III。因此得出结论，化合物III的形成是由这种抗关节炎药物的巯基经金属催化氧化引发的，导致超氧阴离子的形成。一旦形成化合物III，就会开始连锁反应，通过该反应其他D-青霉胺分子的巯基被氧化为二硫化物。同时，髓过氧化物酶的化合物I会被还原为化合物II，氧气会生成超氧阴离子。这一结论得到了实验的支持，实验表明D-青霉胺形成髓过氧化物酶的化合物III取决于氯离子浓度。因此，一种在氯化反应中具有活性的酶中间体（即化合物I）参与了抗关节炎药物生成超氧阴离子的过程。根据本文所述结果，提出D-青霉胺可能通过清除HOCl以及将髓过氧化物酶转化为在HOCl形成中无活性的化合物III，从而在类风湿性关节炎的治疗中发挥其治疗作用。
