REVERSAL OF CYCLOSPORINE-INHIBITED LOW-DENSITY-LIPOPROTEIN RECEPTOR ACTIVITY IN HEPG2 CELLS BY 3-HYDROXY-3-METHYLGLUTARYL COENZYME-A REDUCTASE INHIBITORS

Previously we have shown that cyclosporine inhibits low-density lipopr otein (LDL) catabolism in HepGr2 cells. This inhibition mainly occurs through reduced LDL-receptor activity. 3-Hydroxy-3-methylglutarylcoenz yme A (HMG-CoA) reductase inhibitors up-regulate LDL receptor activity with a subsequent increase in LDL uptake and degradation. In this stu dy, in HepG2 cells, we investigated the effects of HMG-CoA reductase i nhibitors on cellular LDL catabolism in the presence of cyclosporine. Different concentrations of cyclosporine and HMG-CoA reductase inhibit ors, which were within the range of therapeutic concentrations used in humans, were added to the culture medium and the cellular LDL recepto r activity was then measured. The results show that HMG-CoA reductase inhibitors reverse the down-regulatory effect of cyclosporine on LDL r eceptor activity, thus further supporting our previous findings and al so providing a rationale for the already established treatment in cycl osporine-induced hypercholesterolemia with HMG-CoA reductase inhibitor s.