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Abstract：
Bosentan, an endothelin receptor antagonist, has been widely used as a first-line medication for the treatment of pulmonary arterial hypertension (PAH). It has been shown to improve symptoms of hypertension, exercise capacity, and hemodynamics and prolong time to clinical worsening. However, liver dysfunction is a major side effect of bosentan treatment that could hamper the optimal management of patients with PAH. Previously, we demonstrated, using drug metabolism enzymes and transporters analysis, that the carbohydrate sulfotransferase 3 (CHST3) and CHST13 alleles are significantly more frequent in patients with elevated aminotransferases during therapy with bosentan than they are in patients without liver toxicity. In addition, we constructed a pharmacogenomics model to predict bosentan-induced liver injury in patients with PAH using two single-nucleotide polymorphisms and two nongenetic factors. The purpose of the present study was to externally validate the predictive model of bosentan-induced liver toxicity in Japanese patients. We evaluated five cases of patients treated with bosentan, and one presented with liver dysfunction. We applied mutation alleles of CHST3 and CHST13, serum creatinine, and age to our model to predict liver dysfunction. The sensitivity and specificity were calculated as 100% and 50%, respectively. Considering that PAH is a rare disease, multicenter collaboration would be necessary to validate our model.
摘要：
波生坦,内皮素受体拮抗剂,已被广泛用作治疗肺动脉高压（PAH）的一线药物。它已经被证明可以改善高血压的症状，锻炼能力,和血流动力学，延长临床恶化的时间。然而,肝功能障碍是波生坦治疗的主要副作用,可能妨碍PAH患者的最佳治疗.以前,我们展示了，使用药物代谢酶和转运蛋白分析，在使用波生坦治疗期间，转氨酶升高的患者中，碳水化合物磺基转移酶3（CHST3）和CHST13等位基因的频率明显高于无肝脏毒性的患者。此外,我们利用两个单核苷酸多态性和两个非遗传因素构建了药物基因组学模型来预测波生坦诱导的PAH患者肝损伤.本研究的目的是外部验证日本患者波生坦诱导的肝毒性的预测模型。我们评估了5例接受波生坦治疗的患者，其中一人出现肝功能障碍。我们应用CHST3和CHST13的突变等位基因，血清肌酐，和年龄到我们的模型来预测肝功能障碍。敏感性和特异性分别计算为100%和50%，分别。考虑到PAH是一种罕见的疾病，多中心协作对于验证我们的模型是必要的。
