EFFECTS OF MEBENDAZOLE ON PROTEIN-BIOSYNTHESIS AND SECRETION IN HUMAN-DERIVED FIBROBLAST-CULTURES

Previous results of our group revealed chat mebendazole, a broad spect rum anthelmintic drug with antimicrotubular properties, used for the t reatment of liver cirrhosis, decreased total collagen content and bios ynthesis in liver upon treatment. In the present study, we have evalua ted the effects of mebendazole (5-50 mu g/mL) on protein synthesis, se cretion, and deposition in human-derived fibroblast cultures. The resu lts showed a decrease in cell viability (18.5 +/- 0.9%) at 50 mu g/mL. [H-3]Thymidine incorporation diminished gradually with increasing meb endazole concentrations, reaching a plateau (53.67%) between 30 and 50 mu g/mL. In late logarithmic phase cultures, the drug caused a decrea se of [H-3]proline incorporation (43.10%) and collagen biosynthesis (5 8.61%) in the extracellular matrix. This correlated with an increase i n radioactivity in total proteins (51.28%) of the intracellular fracti on. Similar results were obtained when mebendazole was assayed in post confluent fibroblast cultures. The electrophoretic patterns of the ext racellular matrix showed a decrease of radioactive collagenous compone nts (alpha chains and beta dimers). By contrast, in the intracellular fraction an increase of radioactive collagen precursors (pro alpha cha ins) was observed. Immunofluorescence studies and immunotransfer analy sis, using polyclonal anti-type I collagen antibodies, revealed an acc umulation of intracellular collagen which included: collagen pro alpha chains, alpha chains, and low molecular weight peptides. The results obtained suggest that mebendazole interferes with the transcellular mo bilization of proteins, resulting in a decrease of secretion and depos ition of extracellular matrix proteins, and an accumulation of intrace llular collagenous components. The intracellular accumulation of newly synthesized proteins could cause a feedback regulation in fibroblast cultures.