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

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

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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.

抽象的抗抑郁药引起的肝损伤是一个主要的临床问题，多达3％的患者显示肝损害的证据。 Duloxetine（DLX）是一线和大多数规定的抗抑郁药，携带黑色爆炸性的肝毒性警告，但DLX引起的肝损伤的机制在很大程度上尚不清楚。根据我们的初步数据和临床证据，我们假设DLX会导致肝脏损害破坏肝磷脂酰胆碱（LPC）稳态，并抑制DLX代谢增加LPC积累并增强肝毒性。此应用的目的是确定 DLX诱导的肝损伤的机理，以预测和预防DLX肝毒性。我们将通过三个特定目标来追求这一目标：（1）确定修改LPC稳态是否影响DLX 毒性，我们将用磷脂酶A2抑制剂在药理学上阻断LPC生产，并部分阻塞 LPC用LPCAT3 - / - 小鼠遗传消耗。我们将确定DLX毒性并评估LPC水平肝脏和血液。（2）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的异位素LPC和已知的抑制剂在体外和体内的DLX在体外和体内。（3）我们将使用 CYP1A2 - / - ，CYP2D - / - 或L-PORC/C小鼠模型阻止CYP介导的DLX代谢，并确定如何影响LPC水平并增强肝毒性。我们将使用新型的人类肝脏嵌合小鼠，其中小鼠肝P450氧化还原酶是非功能性的，用于评估DLX的I期代谢并确定特定人类P450的抑制剂如何影响DLX的肝毒性。拟议研究的完成应该帮助我们了解DLX肝毒性的潜在机制，并为临床观察到的DLX-rug相互作用。我们的研究策略可以为毒理学群落研究药物引起的肝损伤。这些发现可能会导致新颖的策略 DLX肝毒性在临床中的预测和预防以及DLX临床安全性的改善。