Mechanisms of Liver Toxicity of Anit-Depressant Duloxetine

摘要 抗抑郁药物引起的肝损伤是一个主要的临床问题，高达3%的接受治疗的患者表现出 肝脏受损的证据。度洛西汀(DLX)是一线和最常用的抗抑郁药，携带一种黑色 BOX对其肝脏毒性发出警告，但DLX引起肝损伤的机制仍很大程度上仍不清楚。 根据我们的初步数据和临床证据，我们假设DLX通过以下方式导致肝脏损伤 破坏肝脏溶血磷脂酰胆碱(LPC)动态平衡，抑制DLX代谢 增加LPC蓄积，增强肝毒性。此应用程序的目标是确定 地塞米松致肝损伤的机制(S)使预测和预防地塞米松肝毒性成为可能。我们 我将通过三个具体目标实现这一目标：(1)确定修改LPC动态平衡是否会影响DLX 毒性，我们将用磷脂酶A2抑制剂从药理上阻止LPC的产生，并部分阻断 LPC的摄入与Lpcat3-/-小鼠的遗传有关。我们将确定DLX的毒性并评估LPC水平 肝脏和血液。(2)为了确定DLX导致LPCS积聚的机制，我们将测试 DLX是否抑制LPC降解酶--溶血磷脂酶。我们将测试其机械效应 利用稳定同位素LPCS和已知的抑制剂，在体内外研究DLX对溶血磷脂酶的影响。(3)我们将使用 CyP1A2-/-、Cyp2d-/-或L-Porc/c小鼠模型阻断CyP介导的DLX代谢并确定其作用机制 影响LPC水平，增强肝脏毒性。我们将使用我们的新型人类肝脏嵌合小鼠，在其中 小鼠肝脏P450氧化还原酶无功能，用于评估DLX的I相代谢并确定 特定人P450的抑制剂如何影响DLX的肝毒性。完成拟议的研究 有助于我们了解DLX肝毒性的潜在机制，并为 临床观察到的DLX与药物的相互作用。我们的研究策略可以为 毒理学团体调查药物所致的肝损伤。这些发现可能会导致新的战略 临床预测和预防DLX的肝毒性及改善DLX的临床安全性

ABSTRACT Anti-depressant drug-induced liver injury is a major clinical concern, with up to 3% of patients treated showing evidence of liver damage. Duloxetine (DLX), the first-line and most prescribed antidepressant, carries a black box warning for its hepatotoxicity, but the mechanisms of DLX-induced liver injury remain largely unknown. Based on our preliminary data and clinical evidence, we hypothesize that DLX causes liver damage by disrupting hepatic lysophosphatidylcholine (LPC) homeostasis, and that suppression of DLX metabolism increases LPC accumulation and potentiates hepatotoxicity. The goal of this application is to determine the mechanism(s) of DLX-induced liver injury to enable the prediction and prevention of DLX hepatotoxicity. We will pursue this goal through three specific aims: (1) To determine if modifying LPC homeostasis impacts DLX toxicity, we will block LPC production pharmacologically with phospholipase A2 inhibitors and partially block LPC consumption genetically with Lpcat3-/- mice. We will determine DLX toxicity and assess LPC levels in the liver and blood. (2) To determine the mechanism by which DLX causes accumulation of LPCs, we will test whether DLX inhibits lysophospholipase, the enzyme that degrades LPC. We will test the mechanistic effect of DLX on lysophospholipase in vitro and in vivo using stable-isotope LPCs and known inhibitors. (3) We will use Cyp1a2-/-, Cyp2d-/-, or L-Porc/c mouse models to block CYP-mediated DLX metabolism and determine how this influences LPC levels and potentiates hepatotoxicity. We will use our novel human liver chimeric mice, in which mouse hepatic P450 oxidoreductase is non-functional, to assess Phase I metabolism of DLX and determine how inhibitors for specific human P450s impact hepatotoxicity of DLX. Completion of the proposed studies should help us understand the underlying mechanisms of DLX hepatotoxicity and provide an explanation for clinically observed DLX-drug interactions. Our research strategies could provide a general approach for the toxicological community to investigate drug-induced liver injury. These findings may lead to novel strategies for prediction and prevention of DLX hepatotoxicity in clinic and improvement of the DLX clinical safety profile.