Candidate risk factors and mechanisms for tolvaptan-induced liver injury are identified using a collaborative cross approach

Clinical trials of tolvaptan showed it to be a promising candidate for the treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD) but also revealed potential for idiosyncratic drug-induced liver injury (DILI) in this patient population. To identify risk factors and mechanisms underlying tolvaptan DILI, 8 mice in each of 45 strains of the genetically diverse Collaborative Cross (CC) mouse population were treated with a single oral dose of either tolvaptan or vehicle. Significant elevations in plasma alanine aminotransferase (ALT) were observed in tolvaptan-treated animals in 3 of the 45 strains. Genetic mapping coupled with transcriptomic analysis in the liver was used to identify several candidate susceptibility genes including epoxide hydrolase 2, interferon regulatory factor 3, and mitochondrial fission factor. Gene pathway analysis revealed that oxidative stress and immune response pathways were activated in response to tolvaptan treatment across all strains, but genes inv...

托伐普坦（tolvaptan）的临床试验显示，其作为常染色体显性遗传性多囊肾病（Autosomal Dominant Polycystic Kidney Disease, ADPKD）的治疗候选药物极具潜力，但同时也在该患者群体中发现了引发特发性药物性肝损伤（Idiosyncratic Drug-induced Liver Injury, DILI）的潜在风险。为明确托伐普坦所致DILI的风险因素与潜在机制，研究团队对遗传多样性的协作杂交（Collaborative Cross, CC）小鼠种群的45个品系开展实验，每个品系设置8只小鼠，分别予以单次口服托伐普坦或赋形剂处理。在45个品系中的3个品系里，接受托伐普坦处理的动物观测到血浆丙氨酸氨基转移酶（Alanine Aminotransferase, ALT）水平显著升高。研究通过遗传定位结合肝脏转录组学分析，鉴定出多个候选易感基因，包括环氧化物水解酶2（epoxide hydrolase 2）、干扰素调节因子3（interferon regulatory factor 3）以及线粒体分裂因子（mitochondrial fission factor）。基因通路分析显示，在所有品系中，氧化应激与免疫应答通路均因托伐普坦处理被激活，但相关基因……