THE EFFECT OF CYCLOSPORINE-A ON LDL BINDING BY HUMAN FIBROBLASTS

Hypercholesterolemia is not uncommon as a metabolic side effect of cyc losporin A (CsA) therapy. The precise mechanism of this effect is unkn own. On the other hand, the way CsA crosses the cell membrane is curre ntly unknown. Among others, an interesting hypothesis has been made su ggesting that CsA is bound and internalized by LDL (B,E) receptor conc omitantly with LDL particles, during LDL endocytosis. In order to: 1) evaluate the previous hypothesis, and 2) clarify the mechanism of hype rcholesterolemia after CsA treatment, we preincubated cell cultures of human fibroblasts with CsA in 37 degrees C for 24 hours while identic al material was incubated without the drug. Both cultures were then ex posed to radiolabelled LDL in 4 degrees C for 4 hours. The cells that had been preincubated with CsA bound radioiodinated LDL in a significa ntly lower degree than the non-preincubated ones. If the same phenomen on happens in vivo, it seems that: 1) CsA causes catabolic hypercholes terolemia inhibiting LDL binding by LDL (B,E) receptor and 2) the drug , at least partially, migrates into the cell by a lipid free way.