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Endocrine Research Group, Departments of Medicine and Medical
Biochemistry, the Faculty of Medicine, University of Calgary, Health
Sciences Centre, Calgary, Alberta, Canada,
T2N 4N1 (A.H.T., N.C.W.W.),
and
Novartis Pharmaceuticals Corporation, Summit, New Jersey 07901 (Z.F.S., R.E.S.)
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 µg/kg of the compound. Normal rats required a higher
dose of 1000 µg/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 × 10-12 M and 10-10 M for
thyroid hormone receptors 
1 and 
1, 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.
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