REPRODUCING ABNORMAL CHOLESTEROL-BIOSYNTHESIS AS SEEN IN THE SMITH-LEMLI-OPITZ SYNDROME BY INHIBITING THE CONVERSION OF 7-DEHYDROCHOLESTEROL TO CHOLESTEROL IN RATS

The Smith-Lemli-Opitz syndrome is a recessive inherited disorder chara cterized by neurologic developmental defects and dysmorphic features i n many organs. Recently, abnormal cholesterol biosynthesis with impair ed conversion of 7-dehydrocholesterol to cholesterol has been discover ed in homozygotes, To reproduce the biochemical abnormality, BM 15.766 , a competitive inhibitor of 7-dehydrocholesterol-Delta(7)-reductase, the enzyme that catalyzes the conversion of 7-dehydrocholesterol into cholesterol was fed by gavage to rats. After 14 d, plasma cholesterol concentrations declined from 48 mg/dl to 16 mg/dl and 7-dehydro-choles terol levels rose from trace to 17 mg/dl, Hepatocytes surrounding the central vein developed balloon necrosis. Stimulating cholesterol synth esis with cholestyramine followed by BM 15.766 produced an additional 40% decline (P < 0.05) in plasma cholesterol and 34% increase in 7-deh ydrocholesterol levels compared to the inhibitor alone. Adding 2% chol esterol to the diet during the second week of BM 15.766 treatment incr eased plasma cholesterol threefold and decreased 7-dehydrocholesterol concentrations 55%. Hepatic 3-hydroxy-3-methylglutaryl co-enzyme A (HM G-CoA) reductase activity increased 73% with a 3.9-fold rise in mRNA l evels but cholesterol 7 alpha-hydroxylase activity decreased slightly though mRNA levels increased 1.4 times with BM 15.766 treatment. These results demonstrate that BM 15.766 is a potent inhibitor of 7-dehydro cholesterol-Delta(7)-reductase. The model reproduces abnormal choleste rol biosynthesis as seen in the Smith-Lemli-Opitz syndrome and is usef ul to test different treatment strategies. Stimulating early steps of cholesterol synthesis worsens the biochemical abnormalities while feed ing cholesterol inhibits abnormal synthesis, improves the biochemical abnormalities and prevents liver damage.