Kim Hye-Young H, Korade Zeljka, Tallman Keri A, Liu Wei, Weaver C David, Mirnics Karoly, Porter Ned A
Department of Chemistry and Vanderbilt Institute of Chemical Biology, Vanderbilt University , Nashville, Tennessee 37235, United States.
Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University , Nashville, Tennessee 37235, United States.
Chem Res Toxicol. 2016 May 16;29(5):892-900. doi: 10.1021/acs.chemrestox.6b00054. Epub 2016 Apr 28.
A small library of pharmacologically active compounds (the NIH Clinical Collection) was assayed in Neuro2a cells to determine their effect on the last step in the biosynthesis of cholesterol, the transformation of 7-dehydrocholesterol (7-DHC) to cholesterol promoted by 7-dehydrocholesterol reductase, DHCR7. Of some 727 compounds in the NIH Clinical Collection, over 30 compounds significantly increased 7-DHC in Neuro2a cells when assayed at 1 μM. Active compounds that increased 7-DHC with a Z-score of +3 or greater generally gave rise to modest decreases in desmosterol and increases in lanosterol levels. Among the most active compounds identified in the library were the antipsychotic, antidepressant, and anxiolytic compounds that included perospirone, nefazodone, haloperidol, aripiprazole, trazodone, and buspirone. Fluoxetine and risperidone were also active at 1 μM, and another 10 compounds in this class of pharmaceuticals were identified in the screen at concentrations of 10 μM. Increased levels of 7-DHC are associated with Smith-Lemli-Opitz syndrome (SLOS), a human condition that results from a mutation in the gene that encodes DHCR7. The SLOS phenotype includes neurological deficits and congenital malformations, and it is linked to a higher incidence of autism spectrum disorder. The significance of the current study is that it identifies common pharmacological compounds that may induce a biochemical presentation similar to SLOS. Little is known about the side effects of elevated 7-DHC postdevelopmentally, and the elevated 7-DHC that results from exposure to these compounds may also be a confounder in the diagnosis of SLOS.
在Neuro2a细胞中对一个小型的药理活性化合物库（美国国立卫生研究院临床化合物库）进行了检测，以确定它们对胆固醇生物合成最后一步的影响，即7-脱氢胆固醇还原酶（DHCR7）促进7-脱氢胆固醇（7-DHC）转化为胆固醇的过程。在美国国立卫生研究院临床化合物库中的约727种化合物中，超过30种化合物在1 μM浓度下检测时显著增加了Neuro2a细胞中的7-DHC。Z分数为+3或更高且能增加7-DHC的活性化合物通常会使鲨烯醇适度减少，羊毛甾醇水平升高。在该化合物库中鉴定出的最具活性的化合物包括抗精神病药、抗抑郁药和抗焦虑药，如哌罗匹隆、奈法唑酮、氟哌啶醇、阿立哌唑、曲唑酮和丁螺环酮。氟西汀和利培酮在1 μM时也有活性，并且在该类药物中另外10种化合物在10 μM浓度的筛选中被鉴定出来。7-DHC水平升高与史密斯-莱米-奥皮茨综合征（SLOS）有关，这是一种人类疾病，由编码DHCR7的基因突变引起。SLOS的表型包括神经功能缺陷和先天性畸形，并且它与自闭症谱系障碍的较高发病率有关。当前研究的意义在于它鉴定出了可能诱导类似于SLOS的生化表现的常见药理化合物。关于发育后7-DHC升高的副作用知之甚少，并且接触这些化合物导致的7-DHC升高也可能是SLOS诊断中的一个混淆因素。
