AMIODARONE DECREASES GENE-EXPRESSION OF LOW-DENSITY-LIPOPROTEIN RECEPTOR AT BOTH THE MESSENGER-RNA AND THE PROTEIN LEVEL

Amiodarone, a potent antiarrhythmic drug, decreases plasma and tissue triiodothyronine (T-3) and increases plasma cholesterol levels, resemb ling changes seen during hypothyroidism. The increase of serum cholest erol during amiodarone medication is associated with a decreased expre ssion of the hepatic low-density lipoprotein (LDL) receptor mRNA. To f urther elucidate the mechanism of amiodarone-induced hypercholesterole mia, we investigated whether the decreased mRNA levels are the result of decreased transcription or increased degradation or both, and wheth er protein expression is decreased accordingly. Relative to pair-fed c ontrols, amiodarone treatment increased plasma cholesterol by 69% and decreased expression of the mRNA encoding for the hepatic LDL receptor by 45%. To study this decrease in mRNA, we performed a run-on assay, from which it appears that amiodarone acts by decreasing LDL receptor mRNA expression 2.5-fold at the transcriptional level. The decay rate of liver LDL receptor mRNA, measured at different time points after in jecting actinomycin D, was not different between amiodarone-treated an d control animals (116 +/- 32 minutes and 84 +/- 10 minutes, P=.44). H epatocytes in primary culture isolated from amiodarone-treated and con trol animals were used to determine specific binding of [I-125]-LDL to hepatic LDL receptors. Amiodarone decreased specific LDL binding and Scatchard analysis demonstrated that amiodarone treatment reduced the number of LDL receptors by 69%, without affecting the dissociation con stant (K-d) In conclusion, amiodarone-induced hypercholesterolemia can be explained by decreased transcription of the LDL receptor gene, res ulting in lower mRNA and protein levels. Copyright (C) 1998 by W.B. Sa unders Company.