Cenedella Richard J, Sexton Patricia S, Krishnan Kathiresan, Covey Douglas F
Department of Biochemistry, Kirksville College of Osteopathic Medicine, Kirksville, Missouri 63501, USA.
Lipids. 2005 Jun;40(6):635-40. doi: 10.1007/s11745-005-1426-9.
Treatment of animals or cells with the amphipathic tertiary amine U18666A {3beta-[2-(diethylamino) ethoxy]androst-5-en-17-one} provides models for several human diseases (e.g., cataracts, Niemann-Pick disease, and epilepsy). Although U18666A can inhibit several enzymes in the cholesterol synthesis pathway, we hypothesized that induction of these varied conditions was due to physical effects of the amine rather than to inhibition of specific proteins. To test this possibility we compared the capacity of U18666A and its enantiomer, ent-U18666A, to inhibit net sterol synthesis and induce apoptosis in cultured bovine lens epithelial cells. Nonenantiospecific actions dependent on the physical properties of these mirror image molecules would be identical, but effects dependent upon enantiospecific interactions would be different for the enantiomers. At the same concentrations, both forms of the compound equally inhibited sterol synthesis and induced apoptosis. These observations supported a generalized mechanism of enzyme inhibition such as perturbation of the microenvironment of endoplasmic enzymes and alteration of membrane order, perhaps of the mitochondrial membrane, to explain induction of apoptosis.
用两亲性叔胺U18666A（3β-[2-(二乙氨基)乙氧基]雄甾-5-烯-17-酮）处理动物或细胞可提供多种人类疾病（如白内障、尼曼-匹克病和癫痫）的模型。尽管U18666A可抑制胆固醇合成途径中的多种酶，但我们推测这些不同病症的诱发是由于该胺的物理效应而非特定蛋白质的抑制作用。为了验证这种可能性，我们比较了U18666A及其对映体ent-U18666A在培养的牛晶状体上皮细胞中抑制净甾醇合成和诱导凋亡的能力。依赖于这些镜像分子物理性质的非对映体特异性作用是相同的，但依赖于对映体特异性相互作用的效应对于对映体来说是不同的。在相同浓度下，该化合物的两种形式均能同等程度地抑制甾醇合成并诱导凋亡。这些观察结果支持了一种普遍的酶抑制机制，如内质网酶微环境的扰动以及膜序（可能是线粒体膜的膜序）的改变，以此来解释凋亡的诱导。
