Cytochrome P450 (Version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database
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CYP26C1 Is a Hydroxylase of Multiple Active Retinoids and Interacts with Cellular Retinoic Acid Binding Proteins S
Supplemental material to this article can be found at: http://molpharm.aspetjournals.org/content/suppl/2018/02/23/mol.117.111039.DC1 1521-0111/93/5/489–503$35.00 https://doi.org/10.1124/mol.117.111039 MOLECULAR PHARMACOLOGY Mol Pharmacol 93:489–503, May 2018 Copyright ª 2018 by The American Society for Pharmacology and Experimental Therapeutics CYP26C1 Is a Hydroxylase of Multiple Active Retinoids and Interacts with Cellular Retinoic Acid Binding Proteins s Guo Zhong, David Ortiz, Alex Zelter, Abhinav Nath, and Nina Isoherranen Departments of Pharmaceutics (G.Z., N.I.) and Medicinal Chemistry (D.O., A.N.), School of Pharmacy, and Department of Biochemistry, School of Medicine (A.Z.), University of Washington, Seattle, Washington Received October 31, 2017; accepted February 22, 2018 ABSTRACT Downloaded from The clearance of retinoic acid (RA) and its metabolites is believed orientation of retinoids within the CYP26C1 active site. In compar- to be regulated by the CYP26 enzymes, but the specific roles of ison with other CYP26 family members, CYP26C1 was up to CYP26A1, CYP26B1, and CYP26C1 in clearing active vitamin A 10-fold more efficient in clearing 4-oxo-atRA (intrinsic clearance metabolites have not been defined. The goal of this study was to 153 ml/min/pmol) than CYP26A1 and CYP26B1, suggesting that establish the substrate specificity of CYP26C1, and determine CYP26C1 may be important in clearing this active retinoid. In whether CYP26C1 interacts with cellular retinoic acid binding support of this, CRABPs delivered 4-oxo-atRA and atRA for proteins (CRABPs). CYP26C1 was found to effectively metabo- metabolism by CYP26C1. -
Impaired Hepatic Drug and Steroid Metabolism in Congenital Adrenal
European Journal of Endocrinology (2010) 163 919–924 ISSN 0804-4643 CLINICAL STUDY Impaired hepatic drug and steroid metabolism in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency Dorota Tomalik-Scharte1, Dominique Maiter2, Julia Kirchheiner3, Hannah E Ivison, Uwe Fuhr1 and Wiebke Arlt School of Clinical and Experimental Medicine, Centre for Endocrinology, Diabetes and Metabolism (CEDAM), University of Birmingham, Birmingham B15 2TT, UK, 1Department of Pharmacology, University Hospital, University of Cologne, 50931 Cologne, Germany, 2Department of Endocrinology, University Hospital Saint Luc, 1200 Brussels, Belgium and 3Department of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, 89019 Ulm, Germany (Correspondence should be addressed to W Arlt; Email: [email protected]) Abstract Objective: Patients with congenital adrenal hyperplasia due to P450 oxidoreductase (POR) deficiency (ORD) present with disordered sex development and glucocorticoid deficiency. This is due to disruption of electron transfer from mutant POR to microsomal cytochrome P450 (CYP) enzymes that play a key role in glucocorticoid and sex steroid synthesis. POR also transfers electrons to all major drug- metabolizing CYP enzymes, including CYP3A4 that inactivates glucocorticoid and oestrogens. However, whether ORD results in impairment of in vivo drug metabolism has never been studied. Design: We studied an adult patient with ORD due to homozygous POR A287P, the most frequent POR mutation in Caucasians, and her clinically unaffected, heterozygous mother. The patient had received standard dose oestrogen replacement from 17 until 37 years of age when it was stopped after she developed breast cancer. Methods: Both subjects underwent in vivo cocktail phenotyping comprising the oral administration of caffeine, tolbutamide, omeprazole, dextromethorphan hydrobromide and midazolam to assess the five major drug-metabolizing CYP enzymes. -
Identification and Developmental Expression of the Full Complement Of
Goldstone et al. BMC Genomics 2010, 11:643 http://www.biomedcentral.com/1471-2164/11/643 RESEARCH ARTICLE Open Access Identification and developmental expression of the full complement of Cytochrome P450 genes in Zebrafish Jared V Goldstone1, Andrew G McArthur2, Akira Kubota1, Juliano Zanette1,3, Thiago Parente1,4, Maria E Jönsson1,5, David R Nelson6, John J Stegeman1* Abstract Background: Increasing use of zebrafish in drug discovery and mechanistic toxicology demands knowledge of cytochrome P450 (CYP) gene regulation and function. CYP enzymes catalyze oxidative transformation leading to activation or inactivation of many endogenous and exogenous chemicals, with consequences for normal physiology and disease processes. Many CYPs potentially have roles in developmental specification, and many chemicals that cause developmental abnormalities are substrates for CYPs. Here we identify and annotate the full suite of CYP genes in zebrafish, compare these to the human CYP gene complement, and determine the expression of CYP genes during normal development. Results: Zebrafish have a total of 94 CYP genes, distributed among 18 gene families found also in mammals. There are 32 genes in CYP families 5 to 51, most of which are direct orthologs of human CYPs that are involved in endogenous functions including synthesis or inactivation of regulatory molecules. The high degree of sequence similarity suggests conservation of enzyme activities for these CYPs, confirmed in reports for some steroidogenic enzymes (e.g. CYP19, aromatase; CYP11A, P450scc; CYP17, steroid 17a-hydroxylase), and the CYP26 retinoic acid hydroxylases. Complexity is much greater in gene families 1, 2, and 3, which include CYPs prominent in metabolism of drugs and pollutants, as well as of endogenous substrates. -
Physiologic and Pathophysiologic Roles of Extra Renal Cyp27b1: Case Report T and Review ⁎ Daniel D
Bone Reports 8 (2018) 255–267 Contents lists available at ScienceDirect Bone Reports journal homepage: www.elsevier.com/locate/bonr Physiologic and pathophysiologic roles of extra renal CYP27b1: Case report T and review ⁎ Daniel D. Bikle , Sophie Patzek, Yongmei Wang Department of Medicine, Endocrine Research Unit, Veterans Affairs Medical Center, University of California San Francisco, United States ARTICLE INFO ABSTRACT Keywords: Although the kidney was initially thought to be the sole organ responsible for the production of 1,25(OH)2D via CYP27b1 the enzyme CYP27b1, it is now appreciated that the expression of CYP27b1 in tissues other than the kidney is Immune function wide spread. However, the kidney is the major source for circulating 1,25(OH)2D. Only in certain granulomatous Cancer diseases such as sarcoidosis does the extra renal tissue produce sufficient 1,25(OH)2D to contribute to the cir- Keratinocytes culating levels, generally associated with hypercalcemia, as illustrated by the case report preceding the review. Macrophages Therefore the expression of CYP27b1 outside the kidney under normal circumstances begs the question why, and in particular whether the extra renal production of 1,25(OH)2D has physiologic importance. In this chapter this question will be discussed. First we discuss the sites for extra renal 1,25(OH)2D production. This is followed by a discussion of the regulation of CYP27b1 expression and activity in extra renal tissues, pointing out that such regulation is tissue specific and different from that of CYP27b1 in the kidney. Finally the physiologic significance of extra renal 1,25(OH)2D3 production is examined, with special focus on the role of CYP27b1 in regulation of cellular proliferation and differentiation, hormone secretion, and immune function. -
Transcriptomic Characterization of Fibrolamellar Hepatocellular
Transcriptomic characterization of fibrolamellar PNAS PLUS hepatocellular carcinoma Elana P. Simona, Catherine A. Freijeb, Benjamin A. Farbera,c, Gadi Lalazara, David G. Darcya,c, Joshua N. Honeymana,c, Rachel Chiaroni-Clarkea, Brian D. Dilld, Henrik Molinad, Umesh K. Bhanote, Michael P. La Quagliac, Brad R. Rosenbergb,f, and Sanford M. Simona,1 aLaboratory of Cellular Biophysics, The Rockefeller University, New York, NY 10065; bPresidential Fellows Laboratory, The Rockefeller University, New York, NY 10065; cDivision of Pediatric Surgery, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065; dProteomics Resource Center, The Rockefeller University, New York, NY 10065; ePathology Core Facility, Memorial Sloan-Kettering Cancer Center, New York, NY 10065; and fJohn C. Whitehead Presidential Fellows Program, The Rockefeller University, New York, NY 10065 Edited by Susan S. Taylor, University of California, San Diego, La Jolla, CA, and approved September 22, 2015 (received for review December 29, 2014) Fibrolamellar hepatocellular carcinoma (FLHCC) tumors all carry a exon of DNAJB1 and all but the first exon of PRKACA. This deletion of ∼400 kb in chromosome 19, resulting in a fusion of the produced a chimeric RNA transcript and a translated chimeric genes for the heat shock protein, DNAJ (Hsp40) homolog, subfam- protein that retains the full catalytic activity of wild-type PKA. ily B, member 1, DNAJB1, and the catalytic subunit of protein ki- This chimeric protein was found in 15 of 15 FLHCC patients nase A, PRKACA. The resulting chimeric transcript produces a (21) in the absence of any other recurrent mutations in the DNA fusion protein that retains kinase activity. -
Regulation of Vitamin D Metabolizing Enzymes in Murine Renal and Extrarenal Tissues by Dietary Phosphate, FGF23, and 1,25(OH)2D3
Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2018 Regulation of vitamin D metabolizing enzymes in murine renal and extrarenal tissues by dietary phosphate, FGF23, and 1,25(OH)2D3 Kägi, Larissa ; Bettoni, Carla ; Pastor-Arroyo, Eva M ; Schnitzbauer, Udo ; Hernando, Nati ; Wagner, Carsten A Abstract: BACKGROUND: The 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) together with parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) regulates calcium (Ca2+) and phosphate (Pi) homeostasis, 1,25(OH)2D3 synthesis is mediated by hydroxylases of the cytochrome P450 (Cyp) family. Vitamin D is first modified in the liver by the 25-hydroxylases CYP2R1 and CYP27A1 and further acti- vated in the kidney by the 1-hydroxylase CYP27B1, while the renal 24-hydroxylase CYP24A1 catalyzes the first step of its inactivation. While the kidney is the main organ responsible for circulating levelsofac- tive 1,25(OH)2D3, other organs also express some of these enzymes. Their regulation, however, has been studied less. METHODS AND RESULTS: Here we investigated the effect of several Pi-regulating factors including dietary Pi, PTH and FGF23 on the expression of the vitamin D hydroxylases and the vitamin D receptor VDR in renal and extrarenal tissues of mice. We found that with the exception of Cyp24a1, all the other analyzed mRNAs show a wide tissue distribution. High dietary Pi mainly upregulated the hep- atic expression of Cyp27a1 and Cyp2r1 without changing plasma 1,25(OH)2D3. FGF23 failed to regulate the expression of any of the studied hydroxylases at the used dosage and treatment length. -
Synonymous Single Nucleotide Polymorphisms in Human Cytochrome
DMD Fast Forward. Published on February 9, 2009 as doi:10.1124/dmd.108.026047 DMD #26047 TITLE PAGE: A BIOINFORMATICS APPROACH FOR THE PHENOTYPE PREDICTION OF NON- SYNONYMOUS SINGLE NUCLEOTIDE POLYMORPHISMS IN HUMAN CYTOCHROME P450S LIN-LIN WANG, YONG LI, SHU-FENG ZHOU Department of Nutrition and Food Hygiene, School of Public Health, Peking University, Beijing 100191, P. R. China (LL Wang & Y Li) Discipline of Chinese Medicine, School of Health Sciences, RMIT University, Bundoora, Victoria 3083, Australia (LL Wang & SF Zhou). 1 Copyright 2009 by the American Society for Pharmacology and Experimental Therapeutics. DMD #26047 RUNNING TITLE PAGE: a) Running title: Prediction of phenotype of human CYPs. b) Author for correspondence: A/Prof. Shu-Feng Zhou, MD, PhD Discipline of Chinese Medicine, School of Health Sciences, RMIT University, WHO Collaborating Center for Traditional Medicine, Bundoora, Victoria 3083, Australia. Tel: + 61 3 9925 7794; fax: +61 3 9925 7178. Email: [email protected] c) Number of text pages: 21 Number of tables: 10 Number of figures: 2 Number of references: 40 Number of words in Abstract: 249 Number of words in Introduction: 749 Number of words in Discussion: 1459 d) Non-standard abbreviations: CYP, cytochrome P450; nsSNP, non-synonymous single nucleotide polymorphism. 2 DMD #26047 ABSTRACT Non-synonymous single nucleotide polymorphisms (nsSNPs) in coding regions that can lead to amino acid changes may cause alteration of protein function and account for susceptivity to disease. Identification of deleterious nsSNPs from tolerant nsSNPs is important for characterizing the genetic basis of human disease, assessing individual susceptibility to disease, understanding the pathogenesis of disease, identifying molecular targets for drug treatment and conducting individualized pharmacotherapy. -
Human Cytochrome P450 CYP2A13
[CANCER RESEARCH 60, 5074–5079, September 15, 2000] Human Cytochrome P450 CYP2A13: Predominant Expression in the Respiratory Tract and Its High Efficiency Metabolic Activation of a Tobacco-specific Carcinogen, 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone1 Ting Su, Ziping Bao, Qing-Yu Zhang, Theresa J. Smith, Jun-Yan Hong,2 and Xinxin Ding2 Wadsworth Center, New York State Department of Health, Albany, New York 12201 [T. S., Q-Y. Z., X. D.]; School of Public Health, State University of New York at Albany, Albany, New York [T. S., X. D.]; and Environmental and Occupational Health Sciences Institute, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey 08854 [Z. B., T. J. S., J-Y. H.] ABSTRACT However, heterologously expressed CYP2A7 showed no catalytic activity (17, 18). CYP2A13 cDNA has not been isolated previously; The human CYP2A subfamily comprises three genes, CYP2A6, the reported protein sequence was deduced from the predicted coding CYP2A7, and CYP2A13. CYP2A6 is active toward many carcinogens and region of a CYP2A13 genomic clone (1). On the basis of its sequence is the major coumarin 7-hydroxylase and nicotine C-oxidase in the liver, whereas CYP2A7 is not functional. The function of CYP2A13 has not been features that resemble the nonfunctional CYP2A7 and CYP2A6v1 (a characterized. In this study, a CYP2A13 cDNA was prepared by RNA- genetic variant of CYP2A6) proteins, the CYP2A13 protein was PCR from human nasal mucosa and was translated using a baculovirus predicted to be nonfunctional in coumarin 7-hydroxylation (1). Be- expression system. In a reconstituted system, the expressed CYP2A13 was cause the deduced amino acid sequence of CYP2A13 shares a 95.4% more active than CYP2A6 in the metabolic activation of hexamethylphos- identity with that of CYP2A6 (1), antibodies and chemical probes for phoramide, N,N-dimethylaniline, 2-methoxyacetophenone, and N-nitro- CYP2A6 may interact with CYP2A13. -
A Bayesian Approach to Mediation Analysis Predicts 206 Causal Target Genes in Alzheimer’S Disease
bioRxiv preprint first posted online Nov. 14, 2017; doi: http://dx.doi.org/10.1101/219428. The copyright holder for this preprint (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Title A Bayesian approach to mediation analysis predicts 206 causal target genes in Alzheimer’s disease Authors Yongjin Park+;1;2, Abhishek K Sarkar+;3, Liang He+;1;2, Jose Davila-Velderrain1;2, Philip L De Jager2;4, Manolis Kellis1;2 +: equal contribution. 1: Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA 2: Broad Institute of MIT and Harvard, Cambridge, MA, USA 3: Department of Human Genetics, University of Chicago, Chicago, IL, USA 4: Department of Neurology, Columbia University Medical Center, New York, NY, USA MK: [email protected] Abstract Characterizing the intermediate phenotypes, such as gene expression, that mediate genetic effects on complex dis- eases is a fundamental problem in human genetics. Existing methods utilize genotypic data and summary statistics to identify putative disease genes, but cannot distinguish pleiotropy from causal mediation and are limited by overly strong assumptions about the data. To overcome these limitations, we develop Causal Multivariate Mediation within Extended Linkage disequilibrium (CaMMEL), a novel Bayesian inference framework to jointly model multiple medi- ated and unmediated effects relying only on summary statistics. We show in simulation that CaMMEL accurately distinguishes between mediating and pleiotropic genes unlike existing methods. We applied CaMMEL to Alzheimer’s disease (AD) and found 206 causal genes in sub-threshold loci (p < 10−4). -
Cytochrome P450
COVID-19 is an emerging, rapidly evolving situation. Get the latest public health information from CDC: https://www.coronavirus.gov . Get the latest research from NIH: https://www.nih.gov/coronavirus. Share This Page Search Health Conditions Genes Chromosomes & mtDNA Classroom Help Me Understand Genetics Cytochrome p450 Enzymes produced from the cytochrome P450 genes are involved in the formation (synthesis) and breakdown (metabolism) of various molecules and chemicals within cells. Cytochrome P450 enzymes Learn more about the cytochrome play a role in the synthesis of many molecules including steroid hormones, certain fats (cholesterol p450 gene group: and other fatty acids), and acids used to digest fats (bile acids). Additional cytochrome P450 enzymes metabolize external substances, such as medications that are ingested, and internal substances, such Biochemistry (Ofth edition, 2002): The as toxins that are formed within cells. There are approximately 60 cytochrome P450 genes in humans. Cytochrome P450 System is Widespread Cytochrome P450 enzymes are primarily found in liver cells but are also located in cells throughout the and Performs a Protective Function body. Within cells, cytochrome P450 enzymes are located in a structure involved in protein processing Biochemistry (fth edition, 2002): and transport (endoplasmic reticulum) and the energy-producing centers of cells (mitochondria). The Cytochrome P450 Mechanism (Figure) enzymes found in mitochondria are generally involved in the synthesis and metabolism of internal substances, while enzymes in the endoplasmic reticulum usually metabolize external substances, Indiana University: Cytochrome P450 primarily medications and environmental pollutants. Drug-Interaction Table Common variations (polymorphisms) in cytochrome P450 genes can affect the function of the Human Cytochrome P450 (CYP) Allele enzymes. -
Impaired Hepatic Drug and Steroid Metabolism in Congenital Adrenal
European Journal of Endocrinology (2010) 163 919–924 ISSN 0804-4643 CLINICAL STUDY Impaired hepatic drug and steroid metabolism in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency Dorota Tomalik-Scharte1, Dominique Maiter2, Julia Kirchheiner3, Hannah E Ivison, Uwe Fuhr1 and Wiebke Arlt School of Clinical and Experimental Medicine, Centre for Endocrinology, Diabetes and Metabolism (CEDAM), University of Birmingham, Birmingham B15 2TT, UK, 1Department of Pharmacology, University Hospital, University of Cologne, 50931 Cologne, Germany, 2Department of Endocrinology, University Hospital Saint Luc, 1200 Brussels, Belgium and 3Department of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, 89019 Ulm, Germany (Correspondence should be addressed to W Arlt; Email: [email protected]) Abstract Objective: Patients with congenital adrenal hyperplasia due to P450 oxidoreductase (POR) deficiency (ORD) present with disordered sex development and glucocorticoid deficiency. This is due to disruption of electron transfer from mutant POR to microsomal cytochrome P450 (CYP) enzymes that play a key role in glucocorticoid and sex steroid synthesis. POR also transfers electrons to all major drug- metabolizing CYP enzymes, including CYP3A4 that inactivates glucocorticoid and oestrogens. However, whether ORD results in impairment of in vivo drug metabolism has never been studied. Design: We studied an adult patient with ORD due to homozygous POR A287P, the most frequent POR mutation in Caucasians, and her clinically unaffected, heterozygous mother. The patient had received standard dose oestrogen replacement from 17 until 37 years of age when it was stopped after she developed breast cancer. Methods: Both subjects underwent in vivo cocktail phenotyping comprising the oral administration of caffeine, tolbutamide, omeprazole, dextromethorphan hydrobromide and midazolam to assess the five major drug-metabolizing CYP enzymes. -
CYP11A1 Expression in Bone Is Associated with Aromatase Inhibitor-Related Bone Loss
M RODRI´GUEZ-SANZ and others CYP11A1 is associated with 55:1 69–79 Research AI-related bone loss CYP11A1 expression in bone is associated with aromatase inhibitor-related bone loss M Rodrı´guez-Sanz1, N Garcı´a-Giralt1, D Prieto-Alhambra1,3,4,5, S Servitja6, S Balcells7, R Pecorelli1,2,ADı´ez-Pe´rez1,2, D Grinberg7, I Tusquets6 and X Nogue´s1,2 1IMIM (Hospital del Mar Research Institute), Red Tema´ tica de Investigacio´ n Cooperativa en Envejecimiento y Fragilidad (RETICEF), ISCIII, Carrer del Doctor Aiguader 88, 08003 Barcelona, Spain 2Internal Medicine Department, Hospital del Mar, Universitat Auto` noma de Barcelona, Barcelona, Spain 3IDIAP Jordi Gol Primary Care Research Institute, Universitat Auto` noma de Barcelona, Barcelona, Spain 4Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Oxford NIHR Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK 5MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK Correspondence 6Medical Oncology Department, IMIM (Hospital del Mar Research Institute), Hospital del Mar, Universitat should be addressed Auto` noma de Barcelona, Barcelona, Spain to N Garcı´a-Giralt 7Departament de Gene` tica, Universitat de Barcelona, IBUB, Centro de Investigacio´ n Biome´ dica en Red de Email Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain [email protected] Abstract Aromatase inhibitors (AIs) used as adjuvant therapy in postmenopausal women with Key Words hormone receptor-positive breast cancer cause diverse musculoskeletal side effects that " CYP11A1 include bone loss and its associated fracture. About half of the 391 patients treated with " aromatase inhibitors AIs in the Barcelona–Aromatase induced bone loss in early breast cancer cohort suffered " bone loss a significant bone loss at lumbar spine (LS) and/or femoral neck (FN) after 2 years on " breast cancer Journal of Molecular Endocrinology AI-treatment.