Article detail · 2019
General toxicity assessment of the novel aldose reductase inhibitor cemtirestat
- Year
- 2019
- Type
- article
Data source split
- YÖKSİS YÖKSİS article record
- YÖKSİS venue Interdisciplinary Toxicology
- Catalog match (ISSN) Interdisciplinary Toxicology
- OpenAlex OpenAlex enrichment (abstract, citations, topics)
Abstract
English (OpenAlex)
Abstract Cemtirestat, 3-mercapto-5 H -[1,2,4]-triazino[5,6- b ]indole-5-acetic acid was recently designed and patented as a highly selective and efficient aldose reductase inhibitor endowed with antioxidant activity. The aim of the present study was to assess the general toxicity of cemtirestat using in silico predictions, in vitro and in vivo assays. ProTox-II toxicity prediction software gave 17 “Inactive” outputs, a mild hepatotoxicity score (0.52 probability) along with a predicted LD50 of 1000 mg/kg. Five different cell lines were used including the immortalized mouse microglia BV-2, the primary human fibroblasts VH10, the insulinoma pancreatic β-cells INS-1E, the human colon cancer cells HCT116 and the human immortalized epithelial endometrial cell lines HIEEC. In contrast to the clinically used epalrestat, cemtirestat showed remarkably low cytotoxicity in several different cell culture viability tests such as MTT proliferation assay, neutral red uptake, BrdU incorporation, WST-1 proliferation assay and propidium iodide staining followed by flow cytometry. In a yeast spotting assay, the presence of cemtirestat in incubation of Saccaromyces cerevisiae at concentrations as high as 1000 µM did not affect cell growth rate significantly. In the 120-day repeated oral toxicity study in male Wistar rats with daily cemtirestat dose of 6.4 mg/kg, no significant behavioral alterations or toxicological manifestations were observed in clinical and pathological examinations or in hematological parameters. In summary, these results suggest that cemtirestat is a safe drug that can proceed beyond preclinical studies.
Topics
- Aldose Reductase and Taurine
- Eicosanoids and Hypertension Pharmacology
- Cancer, Hypoxia, and Metabolism
Primary topic Aldose Reductase and Taurine