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：
10328234
负责人：
Feng Li
金额：
$ 42.83万
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 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10328234
关键词：
Acyltransferase Adverse effects Affect Alcohol abuse Antidepressive Agents Biochemical Pathway Biological Markers Blood CYP1A2 gene CYP2D6 gene Cell Death 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 Lead 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 Pharmacology Phase Phosphatidylcholine-Sterol O-Acyltransferase Phospholipase A2 Phosphorylcholine Predisposition Prevention Production Published Comment Research Risk Safety Site Testing Toxic effect Toxicology base drug induced liver injury duloxetine enzyme activity improved in vivo inhibitor insight liver injury metabolomics mouse model novel novel strategies 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.

抽象的抗抑郁药物引起的肝损伤是一个主要的临床问题，高达 3% 的治疗患者出现肝损伤肝损伤的证据。度洛西汀 (DLX) 是一线和最常用的抗抑郁药，带有黑色因其肝毒性而被框警告，但 DLX 引起的肝损伤的机制仍然很大程度上未知。根据我们的初步数据和临床证据，我们假设 DLX 通过以下方式引起肝损伤：破坏肝脏溶血磷脂酰胆碱 (LPC) 稳态，并抑制 DLX 代谢增加 LPC 积累并增强肝毒性。该应用程序的目标是确定 DLX 引起的肝损伤的机制，以预测和预防 DLX 肝毒性。我们将通过三个具体目标来实现这一目标：(1) 确定改变 LPC 稳态是否会影响 DLX 毒性，我们将用磷脂酶 A2 抑制剂从药理上阻断 LPC 的产生，并部分阻断 Lpcat3-/- 小鼠遗传上的 LPC 消耗。我们将确定 DLX 毒性并评估 LPC 水平肝脏和血液。 (2) 为了确定DLX引起LPC积累的机制，我们将测试 DLX 是否抑制溶血磷脂酶（一种降解 LPC 的酶）。我们将测试其机械效应使用稳定同位素 LPC 和已知抑制剂对溶血磷脂酶进行体外和体内 DLX。 (3) 我们将使用 Cyp1a2-/-、Cyp2d-/- 或 L-Porc/c 小鼠模型可阻断 CYP 介导的 DLX 代谢并确定其作用机制影响 LPC 水平并增强肝毒性。我们将使用我们的新型人肝嵌合小鼠，其中小鼠肝脏 P450 氧化还原酶无功能，用于评估 DLX 的 I 期代谢并确定特定人类 P450 抑制剂如何影响 DLX 的肝毒性。完成拟议的研究应该有助于我们了解 DLX 肝毒性的潜在机制并提供解释临床观察到的 DLX 药物相互作用。我们的研究策略可以为毒理学界调查药物引起的肝损伤。这些发现可能会带来新的策略预测和预防DLX临床肝毒性并改善DLX临床安全性。