Limb malformations of rat fetuses exposed to a distal inhibitor of cholesterol biosynthesis.

Triparanol, an inhibitor of desmosterol Delta24 reductase, produces a high rate of limb malformations in rat fetuses exposed at gestational day 10 (gd 10) to a single oral dose (150-200 mg/kg) given to the pregnant dam. AY9944, another efficient distal inhibitor of cholesterol biosynthesis that blocks dehydrocholesterol Delta7 reductase, produces a similar degree of cholesterol depletion but fewer malformations. Gas liquid chromatography-mass spectrometry (GC-MS) profiling of the sterols in the serum of the dams and in extracted embryos shows that in addition to desmosterol Delta24 reductase inhibition the conversion of Delta8 to Delta7 unsaturated sterols is also blocked by Triparanol. Therefore, the inhibitor induces the accumulation of desmosterol (Delta8 cholesten-3beta-ol, 8-dehydrocholesterol) and zymosterol (Delta8, Delta24 cholestadien-3beta-ol) in embryo tissues. The high concentration of the teratogenic drug assayed in the embryos at three successive gestational days (10-30 micro g/g) is thought to cause the blockade in both Delta24 reductase and Delta8-Delta7 isomerase, which results in the particular profile of aberrant sterols. Comparison of the animal model with human syndromes, including limb osseous and skeleton perturbations, suggests a combination of desmosterol and Delta8 unsaturated sterols as being involved in the deleterious influence on limb bone formation.