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Mechanisms of Liver Toxicity of Anit-Depressant Duloxetine

抗抑郁药度洛西汀的肝毒性机制

基本信息

批准号：
10539288
负责人：
Feng Li
金额：
$ 48.32万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10539288
关键词：
Acyltransferase Adverse effects Affect Alcohol abuse Antidepressive Agents Biochemical Pathway Biological Markers Blood CYP1A2 gene CYP2D6 gene Cell Death Induction Cessation of life Cholesterol Clinic Clinical Communities Consumption Cytochrome P450 Data Docking Drug Interactions Drug Metabolic Detoxication Enzymes Esters Generations Glycerylphosphorylcholine Goals Hepatic Hepatocyte Hepatotoxicity Homeostasis Human In Vitro Incidence Knockout Mice Lecithin Liver Liver Failure Lysophosphatidylcholines Lysophospholipase Mediating Metabolism Modeling Mole the mammal Molecular Monitor Mus NADP Nonesterified Fatty Acids Oxidative Stress Oxidoreductase Pathway interactions Patients Pharmaceutical Preparations Phase Phosphatidylcholine-Sterol O-Acyltransferase Phospholipase A2 Phosphorylcholine Predisposition Prevention Production Published Comment Research Risk Safety Site Testing Toxic effect Toxicology drug induced liver injury duloxetine enzyme activity improved in vivo inhibitor insight liver injury metabolomics mouse model novel novel strategies pharmacologic phospholipase A2 inhibitor prevent public health relevance stable isotope toxicant

项目摘要

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.

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