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Cytochrome P450-Dependent Metabolism of Caffeine in Drosophila melanogaster

Caffeine (1, 3, 7-trimethylxanthine), an alkaloid produced by plants, has antioxidant and insecticide properties that can affect metabolism and cognition. In vertebrates, the metabolites derived from caffeine have been identified, and their functions have been characterized. However, the metabolites...

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Autores principales: Coelho, Alexandra, Fraichard, Stephane, Le Goff, Gaëlle, Faure, Philippe, Artur, Yves, Ferveur, Jean-François, Heydel, Jean-Marie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4324904/
https://www.ncbi.nlm.nih.gov/pubmed/25671424
http://dx.doi.org/10.1371/journal.pone.0117328
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author Coelho, Alexandra
Fraichard, Stephane
Le Goff, Gaëlle
Faure, Philippe
Artur, Yves
Ferveur, Jean-François
Heydel, Jean-Marie
author_facet Coelho, Alexandra
Fraichard, Stephane
Le Goff, Gaëlle
Faure, Philippe
Artur, Yves
Ferveur, Jean-François
Heydel, Jean-Marie
author_sort Coelho, Alexandra
collection PubMed
description Caffeine (1, 3, 7-trimethylxanthine), an alkaloid produced by plants, has antioxidant and insecticide properties that can affect metabolism and cognition. In vertebrates, the metabolites derived from caffeine have been identified, and their functions have been characterized. However, the metabolites of caffeine in insects remain unknown. Thus, using radiolabelled caffeine, we have identified some of the primary caffeine metabolites produced in the body of Drosophila melanogaster males, including theobromine, paraxanthine and theophylline. In contrast to mammals, theobromine was the predominant metabolite (paraxanthine in humans; theophylline in monkeys; 1, 3, 7-trimethyluric acid in rodents). A transcriptomic screen of Drosophila flies exposed to caffeine revealed the coordinated variation of a large set of genes that encode xenobiotic-metabolizing proteins, including several cytochromes P450s (CYPs) that were highly overexpressed. Flies treated with metyrapone—an inhibitor of CYP enzymes—showed dramatically decreased caffeine metabolism, indicating that CYPs are involved in this process. Using interference RNA genetic silencing, we measured the metabolic and transcriptomic effect of three candidate CYPs. Silencing of CYP6d5 completely abolished theobromine synthesis, whereas CYP6a8 and CYP12d1 silencing induced different consequences on metabolism and gene expression. Therefore, we characterized several metabolic products and some enzymes potentially involved in the degradation of caffeine. In conclusion, this pioneer approach to caffeine metabolism in insects opens novel perspectives for the investigation of the physiological effects of caffeine metabolites. It also indicates that caffeine could be used as a biomarker to evaluate CYP phenotypes in Drosophila and other insects.
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spelling pubmed-43249042015-02-18 Cytochrome P450-Dependent Metabolism of Caffeine in Drosophila melanogaster Coelho, Alexandra Fraichard, Stephane Le Goff, Gaëlle Faure, Philippe Artur, Yves Ferveur, Jean-François Heydel, Jean-Marie PLoS One Research Article Caffeine (1, 3, 7-trimethylxanthine), an alkaloid produced by plants, has antioxidant and insecticide properties that can affect metabolism and cognition. In vertebrates, the metabolites derived from caffeine have been identified, and their functions have been characterized. However, the metabolites of caffeine in insects remain unknown. Thus, using radiolabelled caffeine, we have identified some of the primary caffeine metabolites produced in the body of Drosophila melanogaster males, including theobromine, paraxanthine and theophylline. In contrast to mammals, theobromine was the predominant metabolite (paraxanthine in humans; theophylline in monkeys; 1, 3, 7-trimethyluric acid in rodents). A transcriptomic screen of Drosophila flies exposed to caffeine revealed the coordinated variation of a large set of genes that encode xenobiotic-metabolizing proteins, including several cytochromes P450s (CYPs) that were highly overexpressed. Flies treated with metyrapone—an inhibitor of CYP enzymes—showed dramatically decreased caffeine metabolism, indicating that CYPs are involved in this process. Using interference RNA genetic silencing, we measured the metabolic and transcriptomic effect of three candidate CYPs. Silencing of CYP6d5 completely abolished theobromine synthesis, whereas CYP6a8 and CYP12d1 silencing induced different consequences on metabolism and gene expression. Therefore, we characterized several metabolic products and some enzymes potentially involved in the degradation of caffeine. In conclusion, this pioneer approach to caffeine metabolism in insects opens novel perspectives for the investigation of the physiological effects of caffeine metabolites. It also indicates that caffeine could be used as a biomarker to evaluate CYP phenotypes in Drosophila and other insects. Public Library of Science 2015-02-11 /pmc/articles/PMC4324904/ /pubmed/25671424 http://dx.doi.org/10.1371/journal.pone.0117328 Text en © 2015 Coelho et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Coelho, Alexandra
Fraichard, Stephane
Le Goff, Gaëlle
Faure, Philippe
Artur, Yves
Ferveur, Jean-François
Heydel, Jean-Marie
Cytochrome P450-Dependent Metabolism of Caffeine in Drosophila melanogaster
title Cytochrome P450-Dependent Metabolism of Caffeine in Drosophila melanogaster
title_full Cytochrome P450-Dependent Metabolism of Caffeine in Drosophila melanogaster
title_fullStr Cytochrome P450-Dependent Metabolism of Caffeine in Drosophila melanogaster
title_full_unstemmed Cytochrome P450-Dependent Metabolism of Caffeine in Drosophila melanogaster
title_short Cytochrome P450-Dependent Metabolism of Caffeine in Drosophila melanogaster
title_sort cytochrome p450-dependent metabolism of caffeine in drosophila melanogaster
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4324904/
https://www.ncbi.nlm.nih.gov/pubmed/25671424
http://dx.doi.org/10.1371/journal.pone.0117328
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