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Defective Cytochrome P450-Catalysed Drug Metabolism in Niemann-Pick Type C Disease
Niemann-Pick type C (NPC) disease is a neurodegenerative lysosomal storage disease caused by mutations in either the NPC1 or NPC2 gene. NPC is characterised by storage of multiple lipids in the late endosomal/lysosomal compartment, resulting in cellular and organ system dysfunction. The underlying m...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4809520/ https://www.ncbi.nlm.nih.gov/pubmed/27019000 http://dx.doi.org/10.1371/journal.pone.0152007 |
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author | Nicoli, Elena-Raluca Al Eisa, Nada Cluzeau, Celine V. M. Wassif, Christopher A. Gray, James Burkert, Kathryn R. Smith, David A. Morris, Lauren Cologna, Stephanie M. Peer, Cody J. Sissung, Tristan M. Uscatu, Constantin-Daniel Figg, William D. Pavan, William J. Vite, Charles H. Porter, Forbes D. Platt, Frances M. |
author_facet | Nicoli, Elena-Raluca Al Eisa, Nada Cluzeau, Celine V. M. Wassif, Christopher A. Gray, James Burkert, Kathryn R. Smith, David A. Morris, Lauren Cologna, Stephanie M. Peer, Cody J. Sissung, Tristan M. Uscatu, Constantin-Daniel Figg, William D. Pavan, William J. Vite, Charles H. Porter, Forbes D. Platt, Frances M. |
author_sort | Nicoli, Elena-Raluca |
collection | PubMed |
description | Niemann-Pick type C (NPC) disease is a neurodegenerative lysosomal storage disease caused by mutations in either the NPC1 or NPC2 gene. NPC is characterised by storage of multiple lipids in the late endosomal/lysosomal compartment, resulting in cellular and organ system dysfunction. The underlying molecular mechanisms that lead to the range of clinical presentations in NPC are not fully understood. While evaluating potential small molecule therapies in Npc1(-/-) mice, we observed a consistent pattern of toxicity associated with drugs metabolised by the cytochrome P450 system, suggesting a potential drug metabolism defect in NPC1 disease. Investigation of the P450 system in the context of NPC1 dysfunction revealed significant changes in the gene expression of many P450 associated genes across the full lifespan of Npc1(-/-) mice, decreased activity of cytochrome P450 reductase, and a global decrease of multiple cytochrome P450 catalysed dealkylation reactions. In vivo drug metabolism studies using a prototypic P450 metabolised drug, midazolam, confirmed dysfunction in drug clearance in the Npc1(-/-) mouse. Expression of the Phase II enzyme uridinediphosphate-glucuronosyltransferase (UGT) was also significantly reduced in Npc1(-/-) mice. Interestingly, reduced activity within the P450 system was also observed in heterozygous Npc1(+/-) mice. The reduced activity of P450 enzymes may be the result of bile acid deficiency/imbalance in Npc1(-/-) mice, as bile acid treatment significantly rescued P450 enzyme activity in Npc1(-/-) mice and has the potential to be an adjunctive therapy for NPC disease patients. The dysfunction in the cytochrome P450 system were recapitulated in the NPC1 feline model. Additionally, we present the first evidence that there are alterations in the P450 system in NPC1 patients. |
format | Online Article Text |
id | pubmed-4809520 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-48095202016-04-05 Defective Cytochrome P450-Catalysed Drug Metabolism in Niemann-Pick Type C Disease Nicoli, Elena-Raluca Al Eisa, Nada Cluzeau, Celine V. M. Wassif, Christopher A. Gray, James Burkert, Kathryn R. Smith, David A. Morris, Lauren Cologna, Stephanie M. Peer, Cody J. Sissung, Tristan M. Uscatu, Constantin-Daniel Figg, William D. Pavan, William J. Vite, Charles H. Porter, Forbes D. Platt, Frances M. PLoS One Research Article Niemann-Pick type C (NPC) disease is a neurodegenerative lysosomal storage disease caused by mutations in either the NPC1 or NPC2 gene. NPC is characterised by storage of multiple lipids in the late endosomal/lysosomal compartment, resulting in cellular and organ system dysfunction. The underlying molecular mechanisms that lead to the range of clinical presentations in NPC are not fully understood. While evaluating potential small molecule therapies in Npc1(-/-) mice, we observed a consistent pattern of toxicity associated with drugs metabolised by the cytochrome P450 system, suggesting a potential drug metabolism defect in NPC1 disease. Investigation of the P450 system in the context of NPC1 dysfunction revealed significant changes in the gene expression of many P450 associated genes across the full lifespan of Npc1(-/-) mice, decreased activity of cytochrome P450 reductase, and a global decrease of multiple cytochrome P450 catalysed dealkylation reactions. In vivo drug metabolism studies using a prototypic P450 metabolised drug, midazolam, confirmed dysfunction in drug clearance in the Npc1(-/-) mouse. Expression of the Phase II enzyme uridinediphosphate-glucuronosyltransferase (UGT) was also significantly reduced in Npc1(-/-) mice. Interestingly, reduced activity within the P450 system was also observed in heterozygous Npc1(+/-) mice. The reduced activity of P450 enzymes may be the result of bile acid deficiency/imbalance in Npc1(-/-) mice, as bile acid treatment significantly rescued P450 enzyme activity in Npc1(-/-) mice and has the potential to be an adjunctive therapy for NPC disease patients. The dysfunction in the cytochrome P450 system were recapitulated in the NPC1 feline model. Additionally, we present the first evidence that there are alterations in the P450 system in NPC1 patients. Public Library of Science 2016-03-28 /pmc/articles/PMC4809520/ /pubmed/27019000 http://dx.doi.org/10.1371/journal.pone.0152007 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication. |
spellingShingle | Research Article Nicoli, Elena-Raluca Al Eisa, Nada Cluzeau, Celine V. M. Wassif, Christopher A. Gray, James Burkert, Kathryn R. Smith, David A. Morris, Lauren Cologna, Stephanie M. Peer, Cody J. Sissung, Tristan M. Uscatu, Constantin-Daniel Figg, William D. Pavan, William J. Vite, Charles H. Porter, Forbes D. Platt, Frances M. Defective Cytochrome P450-Catalysed Drug Metabolism in Niemann-Pick Type C Disease |
title | Defective Cytochrome P450-Catalysed Drug Metabolism in Niemann-Pick Type C Disease |
title_full | Defective Cytochrome P450-Catalysed Drug Metabolism in Niemann-Pick Type C Disease |
title_fullStr | Defective Cytochrome P450-Catalysed Drug Metabolism in Niemann-Pick Type C Disease |
title_full_unstemmed | Defective Cytochrome P450-Catalysed Drug Metabolism in Niemann-Pick Type C Disease |
title_short | Defective Cytochrome P450-Catalysed Drug Metabolism in Niemann-Pick Type C Disease |
title_sort | defective cytochrome p450-catalysed drug metabolism in niemann-pick type c disease |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4809520/ https://www.ncbi.nlm.nih.gov/pubmed/27019000 http://dx.doi.org/10.1371/journal.pone.0152007 |
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