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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：
9913181
负责人：
Feng Li
金额：
$ 44.46万
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/9913181
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 duloxetine enzyme activity improved in vivo inhibitor/antagonist 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.

摘要抗肿瘤药物引起的肝损伤是一个主要的临床问题，高达3%的治疗患者显示肝损伤的证据杜洛西汀（DLX），一线和最处方的抗抑郁药，携带一个黑色的但是DLX诱导的肝损伤的机制在很大程度上仍然未知。基于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。此应用程序的目标是确定研究DLX诱导的肝损伤的机制，以预测和预防DLX肝毒性。我们我将通过三个具体目标来实现这一目标：（1）确定修改LPC稳态是否会影响DLX 毒性，我们将阻断LPC生产与磷脂酶A2抑制剂和部分阻断 Lpcat 3-/-小鼠的LPC消耗遗传。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（降解LPC的酶）。我们将测试使用稳定同位素LPC和已知抑制剂进行的体外和体内DLX对溶血磷脂酶的影响。(3)我们将使用 Cyp 1a 2-/-、Cyp 2d-/-或L-Porc/c小鼠模型，以阻断CYP介导的DLX代谢，并确定这是如何发生的。影响LPC水平并增强肝毒性。我们将使用我们的新型人类肝脏嵌合小鼠，小鼠肝脏P450氧化还原酶无功能，以评估DLX的I期代谢并确定特异性人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，并为以下问题提供解释：临床观察到的DLX-药物相互作用。我们的研究策略可以提供一个通用的方法，毒理学界研究药物性肝损伤。这些发现可能会导致新的策略，预测和预防DLX临床肝毒性，改善DLX临床安全性。