Although L-
triiodothyronine (L-T3) lowers
cholesterol, this
hormone is not used to treat
hypercholesterolemia because of its cardiotoxic effects. Thyromimetics, such as the novel compound
CGS 23425, that mimic the beneficial but lack the detrimental effects of T3, may be useful in the treatment of
hypercholesterolemia. To show that
CGS 23425 has no
cardiotoxicity, atrial contractility and force were both measured and found to be unchanged in rats treated with up to 10 mg/kg
drug. The
lipid lowering actions of this
drug resulted in a 44% decrease in
low-density lipoprotein (
LDL) cholesterol in hypercholesterolemic rats treated with 10 microg/kg of the compound. Normal rats required a higher dose of 1000 microg/kg to elicit a similar 50% reduction in
LDL cholesterol. Both
CGS 23425 or T3 (10 nM) increased the specific binding of 125I-labeled
LDL to Hep G2 cells and increased
LDL receptor number by 44 and 49%, respectively. These data indicate that
CGS 23425 enhances hepatic clearance of serum
LDL cholesterol. Normal and fat-fed animals treated with the
drug showed a dose-dependent increase in
apolipoprotein AI, a
protein that promotes the efflux of
cholesterol from peripheral tissues. Transient transfection of a rat
apolipoprotein AI promoter-
chloramphenicol acetyltransferase construct, in human
hepatoma cells, showed a dose-dependent increase in
chloramphenicol acetyltransferase activity with EC50 values of 2 x 10(-12) M and 10(-10) M for
thyroid hormone receptors beta1 and alpha1, respectively, with maximal responses
at 10(-7) M. These data indicate that
CGS 23425 is a thyromimetic that increases
apolipoprotein AI expression via
thyroid hormone receptor. In summary,
CGS 23425 ameliorates
hypercholesterolemia by increasing
apolipoprotein A1 and the clearance of
LDL cholesterol. Therefore, a compound like
CGS 23425 may be useful for the prevention and reversal of
atherosclerosis.