# Mechanisms of Liver Toxicity of Anit-Depressant Duloxetine

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2021 · $413,566

## Abstract

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.

## Key facts

- **NIH application ID:** 10076827
- **Project number:** 5R01DK121970-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Feng Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $413,566
- **Award type:** 5
- **Project period:** 2020-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10076827

## Citation

> US National Institutes of Health, RePORTER application 10076827, Mechanisms of Liver Toxicity of Anit-Depressant Duloxetine (5R01DK121970-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10076827. Licensed CC0.

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