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Link to original content: http://pubmed.ncbi.nlm.nih.gov/39357336/
Transgenic expression of human cytochrome P450 2E1 in C. elegans and rat PC-12 cells sensitizes to ethanol-induced locomotor and mitochondrial effects - PubMed Skip to main page content
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. 2024 Nov 19:734:150735.
doi: 10.1016/j.bbrc.2024.150735. Epub 2024 Sep 24.

Transgenic expression of human cytochrome P450 2E1 in C. elegans and rat PC-12 cells sensitizes to ethanol-induced locomotor and mitochondrial effects

Hyland C Gonzalez  1 , Kelly R Misare  1 , Tsultrim T Mendenhall  1 , Bethany J Wolf  2 , Patrick J Mulholland  3 , Kacy L Gordon  4 , Jessica H Hartman  5
Affiliations

Transgenic expression of human cytochrome P450 2E1 in C. elegans and rat PC-12 cells sensitizes to ethanol-induced locomotor and mitochondrial effects

Hyland C Gonzalez et al. Biochem Biophys Res Commun. .

Abstract

Chronic alcohol (ethanol) use is increasing in the United States and has been linked to numerous health issues in multiple organ systems including neurological dysfunction and diseases. Ethanol toxicity is mainly driven by the metabolite acetaldehyde, which is generated through three pathways: alcohol dehydrogenase (ADH2), catalase (CAT), and cytochrome P450 2E1 (CYP2E1). ADH2, while the main ethanol clearance pathway in the liver, is not expressed in the mammalian brain, resulting in CAT and CYP2E1 driving local metabolism of ethanol in the central nervous system. CYP2E1 is known to generate reactive metabolites and reactive oxygen species and localizes to the mitochondria (mtCYP2E1) and endoplasmic reticulum (erCYP2E1). We sought to understand the consequences of mtCYP2E1 and erCYP2E1 in the nervous system during acute ethanol exposure. To answer this question, we generated transgenic Caenorhabditis elegans roundworms expressing human CYP2E1 in the mitochondria, endoplasmic reticulum, or both and exposed them to ethanol. We found that at lower concentrations, wild-type and mtCYP2E1-expressing worms had a small but significant inhibition of locomotion, whereas the erCYP2E1-expressing worms showed protection from this inhibition. At higher doses, all strains had reduced locomotion, but the erCYP2E1-expressing worms recovered faster than wild-type controls. CYP2E1 expression, regardless of organellar targeting, reduced mitochondrial respiration in response to ethanol. Similarly, transgenic expression of CYP2E1 in either organelle in PC-12 rat neuronal cell lines sensitized them to ethanol-induced cell death. Together, these findings suggest that subcellular localization of CYP2E1 impacts behavioral effects of ethanol and should be further studied in the mammalian central nervous system.

Keywords: CYP2E1; Caenorhabditis elegans; Endoplasmic reticulum; Ethanol; Metabolism; Mitochondria.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jessica H Hartman reports financial support was provided by National Institutes of Health. Hyland C. Gonzalez reports financial support was provided by National Institutes of Health. Kacy L. Gordon reports financial support was provided by National Institutes of Health. Jessica H. Hartman reports a relationship with Surrozen Inc that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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