Oxidative stress mediates end-organ damage in a novel model of acetaminophen-toxicity in Drosophila

• Type of Material: Article
• Authors: Bejan J Saeedi, Emory University; Sarah Hunter-Chang, Emory University; Liping Luo, Emory University; Kaiyan Li, Emory University; Ken Liu, Emory University; Brian Robinson, Emory University
• Language: English
• Date: 2022-11-11
• Publisher: NATURE PORTFOLIO
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2022
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-022-21156-w
• Title of Journal or Parent Work: SCIENTIFIC REPORTS
• Volume: 12
• Issue: 1
• Start Page: 19309
• End Page: 19309
• Grant/Funding Information: This work was supported by the National Institute for Diabetes and Digestive and Kidney Diseases (F30 award DK117570, T32 award DK108735-01).
• Keywords: HEPATOTOXICITY; INTESTINAL MICROBIOTA; INDUCED LIVER-INJURY; Science & Technology; NRF2; GLUTATHIONE; METABOLISM; MECHANISMS; ACTIVATED-CHARCOAL; Multidisciplinary Sciences; OVERDOSE; REDOX STATE; Science & Technology - Other Topics
• Research Categories: Health Sciences, Pathology

Abstract

Acetaminophen is the most common cause of acute drug-induced liver injury in the United States. However, research into the mechanisms of acetaminophen toxicity and the development of novel therapeutics is hampered by the lack of robust, reproducible, and cost-effective model systems. Herein, we characterize a novel Drosophila-based model of acetaminophen toxicity. We demonstrate that acetaminophen treatment of Drosophila results in similar pathophysiologic alterations as those observed in mammalian systems, including a robust production of reactive oxygen species, depletion of glutathione, and dose-dependent mortality. Moreover, these effects are concentrated in the Drosophila fat body, an organ analogous to the mammalian liver. Utilizing this system, we interrogated the influence of environmental factors on acetaminophen toxicity which has proven difficult in vertebrate models due to cost and inter-individual variability. We find that both increasing age and microbial depletion sensitize Drosophila to acetaminophen toxicity. These environmental influences both alter oxidative stress response pathways in metazoans. Indeed, genetic and pharmacologic manipulations of the antioxidant response modify acetaminophen toxicity in our model. Taken together, these data demonstrate the feasibility of Drosophila for the study of acetaminophen toxicity, bringing with it an ease of genetic and microbiome manipulation, high-throughput screening, and availability of transgenic animals.