D-Penicillamine

D-Penicillamine (DPA, D-Penicillamine, B8692) is an FDA-approved copper chelator for the treatment of Wilson's disease and one of the most widely used agents for reducing systemic copper burden. The thiol and amino groups of D-penicillamine coordinate Cu²⁺ to form stable, highly polar, water-soluble complexes that are readily eliminated through renal excretion. Progressive removal of circulating copper lowers extracellular copper concentrations, thereby promoting the gradual mobilization of excess copper from the liver and other tissues.

Unlike membrane-permeable copper chelators, neither D-penicillamine nor its copper complexes readily cross biological membranes. Consequently, DPA primarily depletes the extracellular copper pool and is less effective than tetrathiomolybdate (TTM) at directly reducing intracellular bioavailable copper in in vitro experiments. Nevertheless, sustained systemic copper depletion suppresses copper-dependent biological processes and can indirectly inhibit cuproptosis by limiting the availability of copper required for intracellular accumulation and mitochondrial toxicity.

The hydrophilic DPA–Cu complexes are efficiently cleared from the body rather than retained within cells, providing a more favorable safety profile for prolonged in vivo administration and chronic animal studies. However, the free thiol group of D-penicillamine readily participates in disulfide exchange with protein cysteine residues and undergoes redox reactions, properties that contribute to its characteristic adverse effects and should be considered when interpreting experimental results.

References:

1. Katerji M, Barada K, Jomaa M, Kobeissy F, Makkawi A-K, Abou-Kheir W and Usta J (2017) Chemosensitivity of U251 Cells to the Co-treatment of D-Penicillamine and Copper: Possible Implications on Wilson Disease Patients. Front. Mol. Neurosci. 10:10. doi: 10.3389/fnmol.2017.00010.