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首页> 外文期刊>The Journal of toxicological sciences >Drug-induced lenticular opacity and accumulation of cholesterol-related substances in the lens cortex of dogs
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Drug-induced lenticular opacity and accumulation of cholesterol-related substances in the lens cortex of dogs

机译：犬晶状体皮质胆固醇相关物质的药物诱导的晶晶不透明度和积累

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TP0446131, developed as an antidepressant agent, was found to cause lenticular opacity in a 13-week repeated-dose study in dogs. Histopathologically, the lenticular opacity was observed as a degeneration of the lens fibers, characterized by irregularity in the ordered arrangement of the fibers which is necessary to maintain the transparency of the lens, and was considered to manifest clinically as cataract. To evaluate the development mechanism of the lenticular opacity, the chemical constituents of the lens, which is known to be associated with the development of cataract, were examined. The results of liquid chromatography-tandem mass spectrometry analysis revealed an increase in the amplitudes of 3 unknown peaks in a dose- and time-dependent manner in the lens, with no remarkable changes in the other chemical components tested. In addition, the content of cholesterol, alterations of which have been reported to be associated with cataract, remained unchanged. The mass spectral data and chromatographic behavior of the 3 peaks indicated that these peaks corresponded to sterol-related substances, and that one of them was 7-dehydrocholesterol, a precursor of cholesterol biosynthesis. This finding suggested that TP0446131 exerts some effects on the cholesterol biosynthesis pathway, which could be involved in the development of the cataracts. Furthermore, increases in the levels of these sterol-related substances were also detected in the serum, and were, in fact, noted prior to the onset of the cataract, suggesting the possibility that these substances in the serum could be used as potential safety biomarkers for predicting the onset of cataract induced by TP0446131.
机译：作为抗抑郁药的TP0446131发现，发现在狗的13周重复剂学研究中引起双凸透明的不透明度。组织病理学上，观察到透镜透明度作为透镜纤维的变性，其特征在于纤维的有序布置中的不规则性，这是维持镜片透明度所必需的，并且被认为是临床上表现为白内障。为了评估透镜透明度的显影机制，检查了已知与白内障的发育相关的晶状体的化学成分。液相色谱 - 串联质谱分析的结果显示，在镜片中的剂量和时间依赖性的方式中显示出3个未知峰的幅度增加，在测试的其他化学成分中没有显着变化。此外，胆固醇的含量，据报道，与白内障有关的胆固醇的含量保持不变。 3峰的质谱数据和色谱行为表明，这些峰对应于甾醇相关物质，其中一个是7-脱羟基醇，一种胆固醇生物合成的前体。该发现表明TP0446131对胆固醇生物合成途径产生一些影响，这可能参与白内障的发展。此外，在血清中也检测到这些与甾醇相关物质的水平的增加，实际上在白内障开始之前注意到，这表明这些物质在血清中可能用作潜在的安全生物标志物用于预测TP0446131诱导的白内障发作。

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