Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
Department of Pharmacognosy, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
Food Chem Toxicol. 2018 Oct;120:112-118. doi: 10.1016/j.fct.2018.07.005. Epub 2018 Jul 4.
Usnic acid is a lichen compound which is extensively studied due to its cytotoxic, antiproliferative, antimicrobial, antiviral, antiprotozoal, and anti-inflammatory activities. Despite a broad spectrum of biological properties, usnic acid is a hepatotoxic agent, thus its potential use as a drug is limited. Certain hepatotoxic drugs may act by generating reactive metabolites that damage the liver. The aim of the study was to predict the biotransformation of usnic acid enantiomers to reactive products using a trapping assay with glutathione in human, rat, and mice liver microsomes. Our results indicate that each enantiomer forms two reactive metabolites; in turn, these metabolites form adducts with glutathione, which may partially explain the toxicity of usnic acid. In silico analysis indicated structural alerts for the generation of reactive metabolites in usnic acid formula. This study proposes a novel mode of the hepatic toxicity of usnic acid enantiomers; it also provides some useful suggestions for designing safer usnic acid derivatives.
松萝酸是一种地衣化合物，由于其具有细胞毒性、抗增殖、抗菌、抗病毒、抗原生动物和抗炎活性，因此受到广泛研究。尽管具有广泛的生物学特性，但松萝酸是一种肝毒性物质，因此其作为药物的潜在用途受到限制。某些肝毒性药物可能通过生成损伤肝脏的反应性代谢物而起作用。本研究旨在使用人、大鼠和小鼠肝微粒体中的谷胱甘肽捕获试验预测松萝酸对映异构体向反应性产物的生物转化。我们的结果表明，每个对映异构体形成两种反应性代谢物；反过来，这些代谢物与谷胱甘肽形成加合物，这可能部分解释了松萝酸的毒性。计算机分析表明松萝酸公式中存在生成反应性代谢物的结构警示。本研究提出了松萝酸对映异构体肝毒性的一种新模式；它还为设计更安全的松萝酸衍生物提供了一些有用的建议。
