Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2024.11.01.621521

Fatty acid-mediated induction of CYP2E1 activity in HepaRG cells is not systematically associated with exacerbated acetaminophen cytotoxicity

Penhoat, C.·Massart, J.·Pinon, G.·Catheline, D.·Rioux, V.·Fromenty, B.·Begriche, K.
View original source ↗Export metadata ↓

Abstract

Hepatic cytochrome P450 2E1 (CYP2E1) is thought to contribute to the pathophysiology of metabolic dysfunction-associated steatotic liver disease (MASLD) formerly known as non-alcoholic fatty liver disease (NAFLD). Indeed, increased activity of CYP2E1 in obese subjects with fatty liver may contribute to higher oxidative stress, mitochondrial dysfunction and the progression to steatohepatitis. Besides, higher CYP2E1 activity in obesity and MASLD is deemed to increase the risk of acetaminophen (APAP)-induced hepatotoxicity because this pain reliever is metabolized by CYP2E1 to N-acetyl-p-benzoquinone imine (NAPQI), a highly toxic metabolite. Although the mechanism of MASLD-associated CYP2E1 induction is still unclear, evidence suggests that hepatic CYP2E1 activity is regulated by fatty acids (FAs). In this study, we investigated the effect of 9 FAs differing by their carbon chain length and their degree of unsaturation on CYP2E1 activity in differentiated HepaRG cells. One-week incubation with palmitic acid (PA), stearic acid (SA) and linoleic acid (LA) induced CYP2E1 activity but only LA exposure induced triglyceride accumulation. APAP hepatotoxicity was then assessed in HepaRG cells cultured with or without PA, SA or LA. Acute APAP cytotoxicity was exacerbated in presence of PA or SA and this was accompanied by more severe mitochondrial dysfunction. These effects were not observed when cells were incubated with LA. Hence, FA-mediated increased CYP2E1 activity in HepaRG cells does not necessarily require steatosis. In addition, FA-mediated CYP2E1 induction does not systematically lead to higher APAP-induced cytotoxicity. By favoring triglyceride accumulation, LA might curb APAP-induced mitochondrial dysfunction and cell death.

Explore related subjects

pharmacology and toxicologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Penhoat, C., Massart, J., Pinon, G., Catheline, D., Rioux, V., Fromenty, B., Begriche, K.. 2024-11-03. Fatty acid-mediated induction of CYP2E1 activity in HepaRG cells is not systematically associated with exacerbated acetaminophen cytotoxicity. https://doi.org/10.1101/2024.11.01.621521

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

PCB-Exposed Gut Microbiota Recapitulate Neurobehavioral Deficits and Reprogram Hippocampal Transcriptomic Signatures

Polychlorinated biphenyls (PCBs) are persistent environmental pollutants associated with developmental neurotoxicity and autism spectrum disorder (ASD). However, whether PCB-induced alterations in gut microbiota contribute to neurodevelopmental toxicity independently of direct chemical exposure remains unclear. Here, we investigated whether transplantation of PCB-associated gut microbiota produces early neurobehavioral alterations and disrupts brain molecular pathways in offspring. Gut microbiota from conventional dams exposed to the Fox River PCB mixture (FRM; 6.0 mg/kg/day) or vehicle were transplanted into germ-free recipient females without direct PCB administration. At postnatal day 7 (P7), offspring underwent ultrasonic vocalization (USV) testing, whole-brain RNA sequencing (n = 4/sex/group), and untargeted serum metabolomics. Untargeted serum metabolomics were also performed in donor dams. PCB-associated fecal microbiota transplantation (FMT) significantly reduced offspring USVs, reproducing effects observed following direct maternal PCB exposure. Brain transcriptomics in offspring identified substantially more differentially expressed genes in males (9,339) than females (1,082), including 512 shared genes. Concordantly regulated genes revealed downregulation of neurotransmitter signaling and ion channel pathways alongside upregulation of RNA processing pathways. Male-associated responses involved altered protein synthesis and neuronal signaling, whereas female-associated responses involved DNA repair and extracellular matrix remodeling. Despite these molecular differences, behavioral responses showed no significant sex-dependent effect. Maternal metabolomics revealed increased bile acids and decreased indole-3-propionic acid, highlighting potential AhR-NF{kappa}B and bile acid-associated signaling mechanisms. Offspring metabolomics further identified alterations in lipid-associated metabolites and metabolic profiles. Collectively, these findings show that transferring PCB-exposed microbiota reproduces early neurobehavioral alterations and induces shared and sex-biased molecular responses, identifying the maternal gut microbiome as a candidate mediator linking PCB exposure to developmental neurotoxicity.

pharmacology and toxicology↗
bioRxiv2026

Cisplatin-triggered sensory dysfunction in NER-defective C. elegans involves GABAergic and cholinergic signaling

Cisplatin (CisPt) is a widely used anticancer drug that causes neurotoxicity as a dose-limiting adverse effect. DNA damage contributes to CisPt-induced neurotoxicity, yet the molecular mechanisms involved remain unclear. Here, we aim to identify pathophysiological mechanisms contributing to DNA damage-driven development of sensory neuronal dysfunction using the 3R-compliant model organism Caenorhabditis elegans. To this end, we employed the nucleotide excision repair (NER)-deficient ercc-1 mutant, which shows enhanced CisPt-induced sensory dysfunction as monitored by the chemotaxis assay, to elucidate drug-induced alterations in neurotransmission and transcriptome. We found that CisPt reduces gamma-aminobutyric acid (GABA) levels in the nematode and that GABA supplementation rescues ercc-1 mutants from CisPt-evoked sensory neurotoxicity, pointing to a neuroprotective function of GABA in the context of our study. Moreover, CisPt impairs the morphological integrity of GABAergic neurons particularly in ercc-1 mutants, which again is rescued by GABA substitution. Conversely, the cholinergic agonist carbachol impairs sensory function and exacerbates the neurotoxic effects of CisPt in ercc-1 mutants, indicating detrimental effects resulting from cholinergic excitation. Transcriptome analysis revealed that CisPt treatment stimulates a broard transcriptional response, including pathways involved in the regulation of neuronal communication, including acetylcholine-mediated neurotransmission, with pronounced effects occurring in the absence of ERCC-1. Based on these finding we suggest impaired GABAergic signaling and the loss of neuronal integrity GABAergic neurons as well as excessive cholinergic excitation as key mechanisms linking CisPt-induced DNA damage in NER defective nematodes to sensory dysfunction. Hence, targeting the balance between GABAergic inhibition and cholinergic excitation is suggested to counteract sensory neurotoxicity triggered by CisPt.

pharmacology and toxicology↗
bioRxiv2026

Mathematical model of phenotypic plasticity predicts interconversion is a drug target for neuroblastoma.

Neuroblastoma is a paediatric cancer arising from the sympathetic nervous system as neural crest cells, made up of noradrenergic (NOR/ADRN/N), mesenchymal like (MES/S), and intermediate (I-type/I) cell types. These cells can interconvert between types, contributing to treatment resistance and relapse. We developed a mathematical model to investigate how interconversion patterns affect the efficacy of phenotype-specific inhibitors. We used three ordinary differential equations to describe the dynamics of the three populations, including logistic growth, interconversion, and drug-induced death. Of the 64 possible interconversion patterns, five reduced the target population: two for N cells and three for S cells. N targeting patterns were more effective with higher interconversion rates, while mesenchymal targeting patterns were more effective with lower interconversion rates. Stability analysis revealed that natural tumour growth was always unstable, but during treatment, N-suppressing patterns combined with an S inhibitor gave the most consistently stable origin. Testing multi-stage and cyclic treatment schedules revealed that N-suppressing patterns with an S inhibitor, followed by an S-suppressing pattern with an N inhibitor, achieved more reliable remission. Three of the five patterns of interest correspond to reported biological plausibility, and known compounds exist to induce most of the required transitions, supporting the clinical relevance of these strategies for improving neuroblastoma treatment outcomes.

pharmacology and toxicology↗