D-penicillamine (D-Pen) is a sulfur compound used in the management of rheumatoid arthritis, Wilson’s disease (WD), and alcohol dependence. Many side effects are associated with its use, particularly after long-term treatment. However, the molecular bases for such side effects are poorly understood. Based on the well-known oxidase activity of hemoproteins, and the participation of catalase in cellular H₂O₂ redox signaling, we posit that D-Pen could inactivate catalase, thus disturbing H₂O₂ levels. Herein, we report on the molecular bases that could partly explain the side effects associated with this drug compound, and we demonstrate that it induces the formation of compound II, a temporarily inactive state of the enzyme, through two distinct mechanisms. Initially, D-Pen reacts with native catalase and/or iron metal ions, used to mimic non heme iron overload observed in long-term treated WD patients, to generate thiyl radicals. These partake into a futile redox cycling, thus producing superoxide radical anions O₂^•- and hydrogen peroxide H₂O₂. Then, either H₂O₂ unexpectedly reacts with native CAT-Fe(II) to produce compound II, or both aforementioned reactive oxygen species intervene into compound II generation through compound I formation then reduction. These findings support evidence that D-Pen could perturb H₂O₂ redox homeostasis through transient but recurring catalase inactivation, which may in part rationalize some deleterious effects observed with this therapeutic agent, as discussed.

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过氧化氢酶与 D-青霉胺相互作用的分子基础：其一些有害作用的合理化

D-青霉胺 (D-Pen) 是一种硫化合物，用于治疗类风湿性关节炎、威尔逊病 (WD) 和酒精依赖。许多副作用与其使用有关，尤其是在长期治疗后。然而，人们对这种副作用的分子基础知之甚少。基于众所周知的血红素蛋白氧化酶活性，以及​​过氧化氢酶参与细胞 H ₂ O ₂氧化还原信号传导，我们假设 D-Pen 可以灭活过氧化氢酶，从而干扰 H ₂ O ₂水平。在此，我们报告了可以部分解释与该药物化合物相关的副作用的分子基础，并证明它通过两种不同的机制诱导化合物 II 的形成，即酶的暂时失活状态。最初，D-Pen 与天然过氧化氢酶和/或铁金属离子反应，用于模拟在长期治疗的 WD 患者中观察到的非血红素铁过载，以生成硫自由基。它们参与无用的氧化还原循环，从而产生超氧自由基阴离子 O ₂ ^•-和过氧化氢 H ₂ O ₂。然后，无论是 H ₂ O ₂出乎意料地与天然 CAT-Fe(II) 反应生成化合物 II，或者上述两种活性氧物种通过化合物 I 的形成然后还原干预化合物 II 的生成。这些发现支持 D-Pen 可以通过短暂但反复发生的过氧化氢酶失活扰乱 H ₂ O ₂氧化还原稳态的证据，这可能在一定程度上解释了使用该治疗剂观察到的一些有害影响，如所讨论的。