Data from: 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 involved in regulation of bile acid homeostasis were most associated with tolvaptan-induced elevations in ALT. Secretory leukocyte peptidase inhibitor (Slpi) mRNA was also induced in the susceptible strains and was associated with increased plasma levels of Slpi protein, suggesting a potential serum marker for DILI susceptibility. In summary, tolvaptan induced signs of oxidative stress, mitochondrial dysfunction, and innate immune response in all strains, but variation in bile acid homeostasis was most associated with susceptibility to the liver response. This CC study has indicated potential mechanisms underlying tolvaptan DILI and biomarkers of susceptibility that may be useful in managing the risk of DILI in ADPKD patients.托伐普坦（tolvaptan）的临床试验结果表明，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应用前景，但同时也在该患者群体中暴露出诱发特发性药物性肝损伤（idiosyncratic drug-induced liver injury, DILI）的潜在风险。为明确托伐普坦诱发DILI的风险因素与潜在分子机制，研究团队对遗传多样性协作杂交（Collaborative Cross, CC）小鼠种群的45个品系开展实验，每个品系选取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个品系的托伐普坦给药组小鼠体内，观察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，鉴定出多个易感候选基因，包括环氧水解酶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）。基因通路分析结果显示，所有品系小鼠在接受托伐普坦给药后均激活了氧化应激与免疫应答通路，但与胆汁酸稳态调控相关的基因与托伐普坦诱导的ALT升高关联最为紧密。分泌型白细胞蛋白酶抑制剂（Secretory leukocyte peptidase inhibitor, Slpi）的mRNA在易感品系中同样被诱导表达，且其血浆蛋白水平也随之升高，提示该蛋白可作为DILI易感性的潜在血清标志物。综上，托伐普坦在所有品系小鼠中均诱导了氧化应激、线粒体功能障碍及固有免疫应答相关的肝脏损伤征象，但胆汁酸稳态的变异与该肝应答的易感性关联最为显著。本项基于CC种群的研究明确了托伐普坦诱发DILI的潜在分子机制，以及可用于辅助评估ADPKD患者DILI风险的易感生物标志物。