Mosedale Merrie, Kim Yunjung, Brock William J, Roth Sharin E, Wiltshire Tim, Eaddy J Scott, Keele Gregory R, Corty Robert W, Xie Yuying, Valdar William, Watkins Paul B
Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, North Carolina 27709.
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina 27599.
Toxicol Sci. 2017 Apr 1;156(2):438-454. doi: 10.1093/toxsci/kfw269.
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.
托伐普坦的临床试验表明，它是治疗常染色体显性多囊肾病（ADPKD）的一个有前景的候选药物，但也揭示了该患者群体中存在特异质性药物性肝损伤（DILI）的可能性。为了确定托伐普坦所致DILI的危险因素和潜在机制，在具有遗传多样性的协作杂交（CC）小鼠群体的45个品系中，每组8只小鼠分别接受单次口服托伐普坦或赋形剂。在45个品系中的3个品系中，接受托伐普坦治疗的动物血浆丙氨酸转氨酶（ALT）显著升高。通过基因定位结合肝脏转录组分析，确定了几个候选易感基因，包括环氧化物水解酶2、干扰素调节因子3和线粒体分裂因子。基因通路分析显示，在所有品系中，氧化应激和免疫反应通路在托伐普坦治疗后均被激活，但参与胆汁酸稳态调节的基因与托伐普坦诱导的ALT升高最为相关。分泌型白细胞蛋白酶抑制剂（Slpi）mRNA在易感品系中也被诱导，并且与Slpi蛋白血浆水平升高相关，提示其可能是DILI易感性的血清标志物。总之，托伐普坦在所有品系中均诱导了氧化应激、线粒体功能障碍和先天性免疫反应的迹象，但胆汁酸稳态的变化与肝脏反应易感性最为相关。这项CC研究揭示了托伐普坦所致DILI的潜在机制以及易感性生物标志物，这可能有助于管理ADPKD患者发生DILI的风险。
