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Publications

Journal Article Research Support, N.I.H., Extramural Ppublish 4 citations

PubMed: 39357336 DOI: 10.1016/j.bbrc.2024.150735

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

Biochem Biophys Res Commun 734:150735

Authors: Hyland C Gonzalez, Kelly R Misare, Tsultrim T Mendenhall, Bethany J Wolf, Patrick J Mulholland, Kacy L Gordon, Jessica H Hartman

Affiliations

  • Dept of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Ave. BSB 501 | MSC 509, Charleston, SC, 29425, USA.
  • Dept of Public Health Sciences, Medical University of South Carolina, 135 Cannon St. Charleston, SC, 29425, USA.
  • Dept of Neuroscience, Charleston Alcohol Research Center, Medical University of South Carolina, 30 Courtenay Drive, Charleston, SC, 29425, USA.
  • Dept of Biology, The University of North Carolina at Chapel Hill, 316 Fordham Hall, Chapel Hill, NC, 27599, USA; UNC Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, 450 West Dr, Chapel Hill, NC, 27599, USA.
  • Dept of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Ave. BSB 501 | MSC 509, Charleston, SC, 29425, USA; Dept of Regenerative Medicine and Cell Biology, Medical University of South Carolina, 173 Ashley Ave. BSB 501 | MSC 509, Charleston, SC, 29425, USA.

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.

MeSH

Cells, Locomotion, Cytochrome P-450 Enzyme System, Cytochromes, Cytochrome P-450 Cyp2E1, Mitochondria, Central Nervous System, Endoplasmic Reticulum, Ethanol, Nervous System

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