Bioactive copper(II) agents and their potential involvement in the treatment of copper deficiency-related orphan diseases

• Published in: Journal of inorganic biochemistry Vol. 247; p. 112334
• Main Authors: Perez, Mariela Gomez, Suarez, Narjara Gonzalez, Annabi, Borhane, Mateescu, Mircea Alexandru
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2023
• Subjects: Amino acid; Copper transporters; Copper:Histidine complexes; Cytochrome c oxidase activity; Paracellular transport, Caco-2 differentiated cells; Ser; HCEM; Copper:Histidine complexes; Im; NR; DMT1; BL; BM; H2O2; CTR1; Amino acid; ATP7B; MD; ATP7A; PBS; Paracellular transport, Caco-2 differentiated cells; MT; CM; Cytochrome c oxidase activity; COX; Copper transporters; AP; SIF; His; SGF; HEPES; ROS; HA; TEER
• DOI: 10.1016/j.jinorgbio.2023.112334
• ISSN: 0162-0134

The deregulation of copper homoeostasis can promote various diseases such as Menkes disease or hypertrophic cardioencephalomyopathy. We have recently synthesized solid copper(II) complexes ([Cu(His)2Cl2] and [Cu(Ser)2]), stable in physiological media and with potential as therapeutic agents. This report describes: i) the biocompatibility of these complexes at concentrations up to 100 μM using a differentiated Caco-2 cells model; ii) their transport across the intestinal epithelium using a transepithelial resistance assay and monitoring the amount of copper complexes at the apical and basolateral sides of the cells. The results suggest that the flow occurs through paracellular routes. The intracellular copper retention was <2.7% with no significant differences in intracellular copper content between 6 h and 48 h, suggesting an early copper retention process. Furthermore, this is the first evidence that demonstrates [Cu(His)2Cl2] and [Cu(Ser)2] induce transcriptional downregulation of the four major copper transporters (CTR1, DMT1, ATP7A, ATP7B), and the upregulation of the metallothionein gene expression. A remarkable finding was the increase in cytochrome c oxidase activity observed after the treatment of differentiated Caco-2 cells with copper(II) complexes at concentrations of 50–100 μM. The understanding of the transport mechanisms of these copper(II) complexes across the intestinal epithelium and of their subsequent biological activities could contribute to the development of optimal pharmaceutical formulations for the therapy of copper deficiency-related diseases. The analysis of the biocompatibility of [Cu(His)2Cl2] and [Cu(Ser)2] complexes, their transport across the intestinal epithelium and their biological activities using a differentiated Caco-2 cells could contribute to the development of pharmaceutical formulations to restore copper levels and rescue cytochrome c oxidase activity in copper deficiency-related diseases like Menkes disease or hypertrophic cardioencephalomyopathy. [Display omitted] •The flow of copper complexes occurs through a paracellular route.•No storage of copper complexes was found within the Caco-2 intestinal cells•Copper complexes induced transcriptional downregulation of copper transporters.•Copper complexes promote the upregulation of the metallothionein gene expression.•[Cu(His)2Cl2] and [Cu(Ser)2] rescue the cytochrome c oxidase activity.