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Transgenic Zebrafish Expressing Rat Cytochrome P450 2E1 (CYP2E1): Augmentation of Acetaminophen-Induced Toxicity in the Liver and Retina

Metabolic activation is the primary cause of chemical toxicity including hepatotoxicity. Cytochrome P450 2E (CYP2E) is involved in this process for many hepatotoxicants, including acetaminophen (APAP), one of the most common analgesics and antipyretics. Although the zebrafish is now used as a model...

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Autores principales: Sato, Yoshinori, Dong, Wenjing, Nakamura, Tatsuro, Mizoguchi, Naohiro, Nawaji, Tasuku, Nishikawa, Miyu, Onaga, Takenori, Ikushiro, Shinichi, Kobayashi, Makoto, Teraoka, Hiroki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9968093/
https://www.ncbi.nlm.nih.gov/pubmed/36835425
http://dx.doi.org/10.3390/ijms24044013
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author Sato, Yoshinori
Dong, Wenjing
Nakamura, Tatsuro
Mizoguchi, Naohiro
Nawaji, Tasuku
Nishikawa, Miyu
Onaga, Takenori
Ikushiro, Shinichi
Kobayashi, Makoto
Teraoka, Hiroki
author_facet Sato, Yoshinori
Dong, Wenjing
Nakamura, Tatsuro
Mizoguchi, Naohiro
Nawaji, Tasuku
Nishikawa, Miyu
Onaga, Takenori
Ikushiro, Shinichi
Kobayashi, Makoto
Teraoka, Hiroki
author_sort Sato, Yoshinori
collection PubMed
description Metabolic activation is the primary cause of chemical toxicity including hepatotoxicity. Cytochrome P450 2E (CYP2E) is involved in this process for many hepatotoxicants, including acetaminophen (APAP), one of the most common analgesics and antipyretics. Although the zebrafish is now used as a model for toxicology and toxicity tests, the CYP2E homologue in zebrafish has not been identified yet. In this study, we prepared transgenic zebrafish embryos/larvae expressing rat CYP2E1 and enhanced green fluorescent protein (EGFP) using a β-actin promoter. Rat CYP2E1 activity was confirmed by the fluorescence of 7-hydroxycoumarin (7-HC), a metabolite of 7-methoxycoumarin that was specific for CYP2 in transgenic larvae with EGFP fluorescence (EGFP [+]) but not in transgenic larvae without EGFP fluorescence (EGFP [−]). APAP (2.5 mM) caused reduction in the size of the retina in EGFP [+] larvae but not in EGFP [−] larvae, while APAP similarly reduced pigmentation in both larvae. APAP at even 1 mM reduced the liver size in EGFP [+] larvae but not in EGFP [−] larvae. APAP-induced reduction of liver size was inhibited by N-acetylcysteine. These results suggest that rat CYP2E1 is involved in some APAP-induced toxicological endpoints in the retina and liver but not in melanogenesis of the developing zebrafish.
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spelling pubmed-99680932023-02-27 Transgenic Zebrafish Expressing Rat Cytochrome P450 2E1 (CYP2E1): Augmentation of Acetaminophen-Induced Toxicity in the Liver and Retina Sato, Yoshinori Dong, Wenjing Nakamura, Tatsuro Mizoguchi, Naohiro Nawaji, Tasuku Nishikawa, Miyu Onaga, Takenori Ikushiro, Shinichi Kobayashi, Makoto Teraoka, Hiroki Int J Mol Sci Article Metabolic activation is the primary cause of chemical toxicity including hepatotoxicity. Cytochrome P450 2E (CYP2E) is involved in this process for many hepatotoxicants, including acetaminophen (APAP), one of the most common analgesics and antipyretics. Although the zebrafish is now used as a model for toxicology and toxicity tests, the CYP2E homologue in zebrafish has not been identified yet. In this study, we prepared transgenic zebrafish embryos/larvae expressing rat CYP2E1 and enhanced green fluorescent protein (EGFP) using a β-actin promoter. Rat CYP2E1 activity was confirmed by the fluorescence of 7-hydroxycoumarin (7-HC), a metabolite of 7-methoxycoumarin that was specific for CYP2 in transgenic larvae with EGFP fluorescence (EGFP [+]) but not in transgenic larvae without EGFP fluorescence (EGFP [−]). APAP (2.5 mM) caused reduction in the size of the retina in EGFP [+] larvae but not in EGFP [−] larvae, while APAP similarly reduced pigmentation in both larvae. APAP at even 1 mM reduced the liver size in EGFP [+] larvae but not in EGFP [−] larvae. APAP-induced reduction of liver size was inhibited by N-acetylcysteine. These results suggest that rat CYP2E1 is involved in some APAP-induced toxicological endpoints in the retina and liver but not in melanogenesis of the developing zebrafish. MDPI 2023-02-16 /pmc/articles/PMC9968093/ /pubmed/36835425 http://dx.doi.org/10.3390/ijms24044013 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sato, Yoshinori
Dong, Wenjing
Nakamura, Tatsuro
Mizoguchi, Naohiro
Nawaji, Tasuku
Nishikawa, Miyu
Onaga, Takenori
Ikushiro, Shinichi
Kobayashi, Makoto
Teraoka, Hiroki
Transgenic Zebrafish Expressing Rat Cytochrome P450 2E1 (CYP2E1): Augmentation of Acetaminophen-Induced Toxicity in the Liver and Retina
title Transgenic Zebrafish Expressing Rat Cytochrome P450 2E1 (CYP2E1): Augmentation of Acetaminophen-Induced Toxicity in the Liver and Retina
title_full Transgenic Zebrafish Expressing Rat Cytochrome P450 2E1 (CYP2E1): Augmentation of Acetaminophen-Induced Toxicity in the Liver and Retina
title_fullStr Transgenic Zebrafish Expressing Rat Cytochrome P450 2E1 (CYP2E1): Augmentation of Acetaminophen-Induced Toxicity in the Liver and Retina
title_full_unstemmed Transgenic Zebrafish Expressing Rat Cytochrome P450 2E1 (CYP2E1): Augmentation of Acetaminophen-Induced Toxicity in the Liver and Retina
title_short Transgenic Zebrafish Expressing Rat Cytochrome P450 2E1 (CYP2E1): Augmentation of Acetaminophen-Induced Toxicity in the Liver and Retina
title_sort transgenic zebrafish expressing rat cytochrome p450 2e1 (cyp2e1): augmentation of acetaminophen-induced toxicity in the liver and retina
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9968093/
https://www.ncbi.nlm.nih.gov/pubmed/36835425
http://dx.doi.org/10.3390/ijms24044013
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