Treatment with d-penicillamine or zinc sulphate affects copper metabolism and improves but not normalizes antioxidant capacity parameters in Wilson disease

Abstract

Copper accumulation in tissues due to a biallelic pathogenic mutation of the gene: ATP7B results in a clinical phenotype known as Wilson disease (WD). Aberrations in copper homeostasis can create favourable conditions for superoxide-yielding redox cycling and oxidative tissue damage. Drugs used in WD treatment aim to remove accumulated copper and normalise the free copper concentration in the blood. In the current study the effect of decoppering treatment on copper metabolism and systemic antioxidant capacity parameters was analyzed. Treatment naïve WD patients (TNWD) (n = 33), those treated with anti-copper drugs (TWD) (n = 99), and healthy controls (n = 99) were studied. Both TNWD and TWD patients characterised with decreased copper metabolism parameters, as well as decreased total antioxidant potential (AOP), glutathione (GSH) level, activity of catalase, glutathione peroxidase (GPx), and S-transferase glutathione, compared to controls. TWD patients had significantly lower copper metabolism parameters, higher total AOP and higher levels of GSH than TWD individuals; however, no difference was observed between these two patient groups with respect to the rest of the antioxidant capacity parameters. Patients who had undergone treatment with d-penicillamine or zinc sulphate did not differ with respect to copper metabolism or antioxidant capacity parameters, with the exception of GPx that was lower in d-penicillamine treated individuals. These data suggest that anti-copper treatment affects copper metabolism as well as improves, but does not normalize, natural antioxidant capacity in patients with WD. We propose to undertake studies aimed to evaluate the usefulness of antioxidants as well as selenium as a supplemental therapy in WD.

Copper interferes with selenoprotein synthesis and activity

“…In another clinical study on Wilson's disease, treatment naive patients were compared with patients receiving Cu reducing therapy. In those patients, higher serum Cu levels were associated with higher and not lower whole blood GPX activity [ 69 ]. For Cu effects on TXNRD activity, little data is available from the literature.…”

The Relevance of Selenium Status in Rheumatoid Arthritis

“…In this sense, supplementation with Se is recommended for the suppression of the side effects of treatment with D-penicillamine. Nevertheless, like auranofin, its administration has been displaced by methotrexate [ 106 , 107 ]. Regarding prednisolone in the treatment of RA, it was related to plasma depression of Se by an unknown mechanism [ 108 ]; however, the lack of information on the duration of administration of prednisolone in these patients precludes the conclusion of this event [ 109 ].…”

Chemosensitivity of U251 Cells to the Co-treatment of D-Penicillamine and Copper: Possible Implications on Wilson Disease Patients

“…Free and loosely bound copper contributes to free radical production (Ogihara et al, 1995 ) that perturbs antioxidants' status and induces neurodegenerative disorders in humans (Gilgun-Sherki et al, 2001 ). However, evaluation of the systemic antioxidant potential of WD patients treated with de-coppering agents, such as PA, showed some improvement without restoring the normal capacity of antioxidant parameters (Gromadzka et al, 2014 ). The exact mechanisms underlying the worsening of the neurological symptoms in PA-treated WD patients remain unclear and not fully elucidated yet, requiring further investigations.…”