Treatment of the cholesterol biosynthetic defect in Smith-Lemli-Opitz syndrome reproduced in rats by BM 15.766

Gastroenterology. 1995 Oct;109(4):1301-7. doi: 10.1016/0016-5085(95)90592-8.


Background & aims: The Smith-Lemli-Opitz syndrome is a recessive inherited disorder characterized by neurological developmental defects and dysmorphic features with a defect in cholesterol synthesis at the conversion of 7-dehydrocholesterol to cholesterol. BM 15.766 inhibits 7-dehydrocholesterol-delta 7-reductase and reproduces the biochemical defect. The aim of this study was to investigate the effects of cholesterol, cholic acid, and lovastatin feeding on rats fed BM 15.766.

Methods: Plasma cholesterol and 7-dehydrocholesterol concentrations were related to the hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.

Results: With the inhibitor treatment, plasma cholesterol concentrations decreased 67%; 7-dehydrocholesterol concentrations increased from trace to 17 mg/dL; and hepatic HMG-CoA reductase activity and messenger RNA levels were stimulated 74% and two times, respectively. In inhibitor-treated rats, feeding cholesterol increased plasma cholesterol concentrations 3.7 times, decreased 7-dehydrocholesterol concentrations 88%, and reduced elevated HMG-CoA reductase activity and messenger RNA levels 74% and 49%. Feeding cholic acid increased plasma cholesterol without reducing 7-dehydrocholesterol concentrations. The combination of cholic acid and cholesterol enhanced plasma cholesterol 9.5 times without decreasing 7-dehydrocholesterol levels. Feeding lovastatin depressed plasma cholesterol further without reducing 7-dehydrocholesterol levels.

Conclusions: Cholesterol is essential to correct abnormal cholesterol synthesis induced by BM 15.766 in rats by expanding the pool and inhibiting HMG-CoA reductase. Neither cholic acid nor lovastatin are effective separately, but cholic acid plus cholesterol may offer some additional benefit.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acyl Coenzyme A / analysis
  • Animals
  • Cholesterol / biosynthesis
  • Cholesterol / blood
  • Cholesterol / therapeutic use*
  • Cholic Acid
  • Cholic Acids / therapeutic use*
  • Dehydrocholesterols / blood
  • Disease Models, Animal
  • Liver / enzymology
  • Lovastatin / therapeutic use*
  • Male
  • Microsomes, Liver / enzymology
  • Oxidoreductases / antagonists & inhibitors
  • Oxidoreductases Acting on CH-CH Group Donors*
  • Piperazines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Smith-Lemli-Opitz Syndrome / chemically induced
  • Smith-Lemli-Opitz Syndrome / drug therapy*
  • Smith-Lemli-Opitz Syndrome / metabolism


  • Acyl Coenzyme A
  • Cholic Acids
  • Dehydrocholesterols
  • Piperazines
  • 3-hydroxy-3-methylglutaryl-coenzyme A
  • BM 15766
  • Cholesterol
  • Lovastatin
  • 7-dehydrocholesterol
  • Oxidoreductases
  • Oxidoreductases Acting on CH-CH Group Donors
  • 7-dehydrocholesterol reductase
  • Cholic Acid