Enhanced cyto- and genotoxicity of tetracycline in Wilson disease fibroblasts

Tetracycline (TC) exerts DNA damaging properties which are accelerated in the presence of copper(II). Thereby, reactive oxygen species are generated. We investigated, if copper-accumulating cells show a higher sensitivity to TC compared to normal cells. Fibroblasts with an increased copper content were derived from patients of two genetic disorders, Wilson disease (WD) and Menkes disease (MD). Cytotoxic and genotoxic effects of TC were investigated in different human fibroblasts. The inhibition of cell growth by TC was measured in two normal fibroblast lines, fibroblast lines of two patients with WD and one patient with MD. While TC inhibited cell growth at similar concentrations in normal fibroblasts and the MD fibroblasts, the WD cells were much more sensitive. Furthermore, an increased inhibition of DNA synthesis and an enhnaced induction of unscheduled DNA synthesis (UDS) was found in WD cells after a TC-treatment compared to normal cells.