Limb malformations of rat fetuses exposed to a distal inhibitor of cholesterol biosynthesis
Limb malformations of rat fetuses exposed to a distal inhibitor of cholesterol biosynthesis
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DOI：
10.1194/jlr.m200082-jlr200
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发表时间：
2002-08-01
影响因子：
6.5
通讯作者：
Roux, C
中科院分区：
文献类型：
--
作者：
Chevy, F;Illien, F;Roux, C
Triparano是一种Desmosterol Delta24还原酶抑制剂，在妊娠第10天(Gd 10)给怀孕母鼠单剂量口服(150-200 mg/kg)的大鼠中，会导致高肢体畸形率。AY9944是另一种有效的胆固醇生物合成末端抑制剂，可以阻断脱氢胆固醇Delta7还原酶，产生类似程度的胆固醇消耗，但畸形较少。用气相色谱-质谱仪(GC-MS)对水坝血清和胚胎中的甾醇进行分析，结果表明，除了桥粒甾醇Delta24还原酶抑制外，Triparol还能阻止Delta8向Delta7不饱和甾醇的转化。因此，该抑制物可诱导胚胎组织中桥粒甾醇(Delta8 Cholesten-3 beta-ol，8-脱氢胆固醇)和酵素(zymosterol，Delta8，Delta24 Cholestadien-3 beta-ol)的积累。在胚胎中连续三天(10-30µg/g)检测的高浓度致畸药物被认为是导致Delta24还原酶和Delta8-Delta7异构酶被阻断的原因，这导致了异常甾醇的特殊图谱。动物模型与人类综合征(包括四肢骨质和骨骼紊乱)的比较表明，Desmosterol和Delta8不饱和甾醇的组合参与了对四肢骨形成的有害影响。-Chevy，F.，F.Illien，C.Wolf和C.Roux暴露于胆固醇生物合成远端抑制剂的大鼠胚胎肢体畸形。脂类研究，2002年。43：1192-1200。
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 mug/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.-Chevy, F., F. Illien, C. Wolf, and C. Roux. Limb malformations of rat fetuses exposed to a distal inhibitor of cholesterol biosynthesis. Lipid Res. 2002. 43: 1192-1200.