title: Defective Cytochrome P450-Catalysed Drug Metabolism in Niemann-Pick Type C Disease.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
authors.forename: Elena-Raluca
authors.initials: ER
authors.lastname: Nicoli
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
authors.forename: Nada
authors.initials: N
authors.lastname: Al Eisa
authors.affiliation: Section of Molecular Dysmorphology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, United States of America.
authors.forename: Celine V M
authors.initials: CV
authors.lastname: Cluzeau
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, United Kingdom.|Section of Molecular Dysmorphology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, United States of America.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Wassif
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Gray
authors.affiliation: Section of Molecular Dysmorphology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, United States of America.
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Burkert
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
authors.forename: David A
authors.initials: DA
authors.lastname: Smith
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
authors.forename: Lauren
authors.initials: L
authors.lastname: Morris
authors.affiliation: Section of Molecular Dysmorphology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, United States of America.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Cologna
authors.affiliation: Clinical Pharmacology Program, Medical Oncology Branch, National Cancer Institute, Department of Health and Human Services, Bethesda, Maryland, United States of America.
authors.forename: Cody J
authors.initials: CJ
authors.lastname: Peer
authors.affiliation: Clinical Pharmacology Program, Medical Oncology Branch, National Cancer Institute, Department of Health and Human Services, Bethesda, Maryland, United States of America.
authors.forename: Tristan M
authors.initials: TM
authors.lastname: Sissung
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, United Kingdom.|Department of Cellular and Molecular Biology, University of Medicine and Pharmacy of Craiova, Craiova, Romania.
authors.forename: Constantin-Daniel
authors.initials: CD
authors.lastname: Uscatu
authors.affiliation: Clinical Pharmacology Program, Medical Oncology Branch, National Cancer Institute, Department of Health and Human Services, Bethesda, Maryland, United States of America.
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.affiliation: Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, United States of America.
authors.forename: William J
authors.initials: WJ
authors.lastname: Pavan
authors.affiliation: School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Vite
authors.affiliation: Section of Molecular Dysmorphology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, United States of America.
authors.forename: Forbes D
authors.initials: FD
authors.lastname: Porter
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
authors.forename: Frances M
authors.initials: FM
authors.lastname: Platt
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002415:Cats; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D019587:Dietary Supplements; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D008874:Midazolam / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D023421:Models, Animal; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000188:drug therapy* / Q000473:pathology; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D014580:Ursodeoxycholic Acid / Q000378:metabolism / Q000494:pharmacology; D047392:beta-Cyclodextrins / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D014580:Ursodeoxycholic Acid; D003577:Cytochrome P-450 Enzyme System; D008874:Midazolam