Tri-iodothyronine prevents the amiodarone-induced decrease in the expression of the liver low-density lipoprotein receptor gene.
Treatment with amiodarone, a potent antiarrhythmic drug, is associated with a dose-dependent increase in plasma cholesterol resulting from a decreased number of liver low-density lipoprotein (LDL) receptors. Similar changes occur in hypothyroidism, and it has been suggested that amiodarone acts via induction of a local 'hypothyroid-like' state in extrathyroidal tissues. The present study was designed to evaluate whether exogenous tri-iodothyronine (T3) could prevent the effects of amiodarone on LDL cholesterol. Rats were treated for 14 days with water, amiodarone 10 mg/100 g body weight (BW), or amiodarone and 2.5, 5 or 10 micrograms T3/100 g BW respectively. Relative to controls, amiodarone increased plasma LDL cholesterol by 31% and decreased liver LDL receptor mRNA by 56% and protein by 45%; liver T3 content was reduced by 21%. Addition of T3 to the treatment with amiodarone dose-dependently reversed all these changes, with a return to control values of plasma cholesterol and the number of liver LDL receptors, although LDL receptor mRNA remained slightly lower. Treatment of rats for 14 days with T3 alone (5 micrograms/100 g BW) decreased plasma LDL cholesterol by 19% and increased liver LDL receptor mRNA by 41%. In conclusion, T3 prevents the amiodarone-induced changes in plasma LDL cholesterol and liver LDL receptor gene expression. These findings suggest that the inhibitory effect of amiodarone on LDL receptor gene expression is mediated by T3-dependent pathways.
Hudig
F
F
Department of Endocrinology, University of Amsterdam, The Netherlands.
Bakker
O
O
Wiersinga
W M
WM
D000638:Amiodarone / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D008078:Cholesterol, LDL / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D014284:Triiodothyronine / Q000378:metabolism / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D008078:Cholesterol, LDL; D012333:RNA, Messenger; D011973:Receptors, LDL; D014284:Triiodothyronine; D000638:Amiodarone