You Dahea, Lyn-Cook Lascelles E, Gatti Daniel M, Bell Natalie, Mayeux Philip R, James Laura P, Mattes William B, Larson Gary J, Harrill Alison H
Division of the National Toxicology Program, The National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Graduate Program in Interdisciplinary Biomedical Sciences, The University of Arkansas for Medical Sciences and Arkansas Children's Research Institute, Little Rock, Arkansas 72205.
Toxicol Sci. 2020 Jun 1;175(2):220-235. doi: 10.1093/toxsci/kfaa037.
Zileuton is an orally active inhibitor of leukotriene synthesis for maintenance treatment of asthma, for which clinical usage has been associated with idiosyncratic liver injury. Mechanistic understanding of zileuton toxicity is hampered by the rarity of the cases and lack of an animal model. A promising model for mechanistic study of rare liver injury is the Diversity Outbred (J:DO) mouse population, with genetic variation similar to that found in humans. In this study, female DO mice were administered zileuton or vehicle daily for 7 days (i.g.). Serum liver enzymes were elevated in the zileuton group, with marked interindividual variability in response. Zileuton exposure-induced findings in susceptible DO mice included microvesicular fatty change, hepatocellular mitosis, and hepatocellular necrosis. Inducible nitric oxide synthase and nitrotyrosine abundance were increased in livers of animals with necrosis and those with fatty change, implicating nitrosative stress as a possible injury mechanism. Conversely, DO mice lacking adverse liver pathology following zileuton exposure experienced decreased hepatic concentrations of resistin and increased concentrations of insulin and leptin, providing potential clues into mechanisms of toxicity resistance. Transcriptome pathway analysis highlighted mitochondrial dysfunction and altered fatty acid oxidation as key molecular perturbations associated with zileuton exposure, and suggested that interindividual differences in cytochrome P450 metabolism, glutathione-mediated detoxification, and farnesoid X receptor signaling may contribute to zileuton-induced liver injury (ZILI). Taken together, DO mice provided a platform for investigating mechanisms of toxicity and resistance in context of ZILI which may lead to targeted therapeutic interventions.
齐留通是一种口服活性白三烯合成抑制剂，用于哮喘的维持治疗，其临床应用与特异质性肝损伤有关。由于病例罕见且缺乏动物模型，对齐留通毒性的机制理解受到阻碍。一个有前景的用于罕见肝损伤机制研究的模型是多样性远交（J:DO）小鼠群体，其基因变异与人类相似。在本研究中，雌性DO小鼠每天经口给予齐留通或赋形剂，持续7天。齐留通组血清肝酶升高，个体反应存在显著差异。齐留通暴露在易感DO小鼠中引起的发现包括微泡性脂肪变、肝细胞有丝分裂和肝细胞坏死。诱导型一氧化氮合酶和硝基酪氨酸丰度在有坏死和有脂肪变的动物肝脏中增加，提示亚硝化应激可能是一种损伤机制。相反，齐留通暴露后无肝脏不良病理改变的DO小鼠肝脏中抵抗素浓度降低，胰岛素和瘦素浓度升高，为毒性抵抗机制提供了潜在线索。转录组通路分析突出了线粒体功能障碍和脂肪酸氧化改变是与齐留通暴露相关的关键分子扰动，并表明细胞色素P450代谢、谷胱甘肽介导的解毒和法尼酯X受体信号的个体差异可能导致齐留通诱导的肝损伤（ZILI）。综上所述，DO小鼠为研究ZILI背景下的毒性和抵抗机制提供了一个平台，这可能会导致有针对性的治疗干预。
