Department of Pharmaceutical Sciences (Unit of Public Health), University of Perugia, Via del Giochetto, 06122 Perugia, Italy.
Seleno Therapeutics Pty. Ltd., Brighton East, Victoria 3187, Australia.
Toxicology. 2023 Nov;499:153663. doi: 10.1016/j.tox.2023.153663. Epub 2023 Nov 2.
1,4-Anhydro-4-seleno-D-talitol (SeTal) is a highly water-soluble selenosugar with interesting antioxidant and skin-tissue-repair properties; it is highly stable in simulated gastric and gastrointestinal fluids and is a potential pharmaceutical ingredient that may be administered orally. Hepatic toxicity is often a major problem with novel drugs and can result in drug withdrawal from the market. Predicting hepatotoxicity is therefore essential to minimize late failure in the drug-discovery process. Herein, we report in vitro studies to evaluate the cytotoxic and genotoxic potential of SeTal in HepG2 and hepatocyte-like differentiated HepaRG cells. Except for extremely high concentrations (10 mM, 68 h-treatment in HepG2), SeTal did not affect the viability of each cell type. While the highest examined concentrations (0.75 and 1 mM in HepG2; 1 mM in HepaRG) were observed to induce primary DNA damage, SeTal did not exhibit clastogenic or aneugenic activity toward either HepG2 or HepaRG cells. Moreover, no significant cytostasis variations were observed in any experiment. The clearly negative results observed in the CBMN test suggest that SeTal might be used as a potential active pharmaceutical ingredient. The present study will be useful for the selection of non-toxic concentrations of SeTal in future investigations.
1,4-脱水-4-硒代-D-山梨醇(SeTal)是一种高度水溶性的硒代糖,具有有趣的抗氧化和皮肤组织修复特性;它在模拟胃液和胃肠道液中高度稳定,是一种具有潜在药用价值的成分,可能通过口服给药。新型药物通常会引起肝毒性,这可能导致药物从市场上撤出。因此,预测肝毒性对于最大限度地减少药物发现过程中的后期失败至关重要。在此,我们报告了体外研究,以评估 SeTal 在 HepG2 和肝样分化 HepaRG 细胞中的细胞毒性和遗传毒性潜力。除了极高的浓度(10 mM,68 h 在 HepG2 中处理)外,SeTal 不会影响每种细胞类型的活力。虽然观察到最高浓度(HepaRG 中的 0.75 和 1 mM;HepaRG 中的 1 mM)诱导原发性 DNA 损伤,但 SeTal 对 HepG2 或 HepaRG 细胞均没有表现出致裂或致畸活性。此外,在任何实验中均未观察到明显的细胞抑制变化。CBMN 试验中观察到的明显阴性结果表明,SeTal 可用作潜在的活性药物成分。本研究将有助于在未来的研究中选择无毒浓度的 SeTal。