1. Drug-induced lenticular opacity and accumulation of cholesterol-related substances in the lens cortex of dogs
- Author
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Kazunari Sugihara, Yasuhiro Kurihara, Hiroshi Iwasaki, Junya Morita, Yutaka Nakanishi, Tomoko Izumi, Satoshi Tsuji, Masaki Wakamatsu, Kohnosuke Kinoshita, Minoru Sasaki, Tomohiro Nishimoto, and Kyohei Kamio
- Subjects
Drug ,Male ,medicine.medical_specialty ,media_common.quotation_subject ,Degeneration (medical) ,010501 environmental sciences ,Toxicology ,030226 pharmacology & pharmacy ,01 natural sciences ,Cataract ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Dehydrocholesterols ,Cataracts ,Tandem Mass Spectrometry ,Internal medicine ,medicine ,Humans ,Lenticular opacity ,0105 earth and related environmental sciences ,media_common ,Dose-Response Relationship, Drug ,Chemistry ,Cholesterol ,Lens cortex ,Lens Cortex, Crystalline ,medicine.disease ,eye diseases ,Lens Fiber ,Antidepressive Agents ,medicine.anatomical_structure ,Endocrinology ,Lens (anatomy) ,sense organs ,Biomarkers ,Chromatography, Liquid - Abstract
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.
- Published
- 2020