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Pharmacogenomics of human P450 oxidoreductase

English title Pharmacogenomics of human P450 oxidoreductase
Applicant Pandey Amit V.
Number 113719
Funding scheme Project funding (Div. I-III)
Research institution Theodor Kocher Institut Universität Bern
Institution of higher education University of Berne - BE
Main discipline Endocrinology
Start/End 01.07.2007 - 30.06.2011
Approved amount 227'000.00
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Keywords (6)

cytochrome P450; P450 oxidoreductase; POR; CPR; steroidogenesis; drug metabolism

Lay Summary (English)

Lead
Lay summary
Cytochrome P450 enzymes are responsible for metabolism of drugs and xenobiotics in the liver and biosynthesis of steroid hormones in the reproductive tissues. There are two distinct types of P450 enzymes; type 1 enzymes are found in mitochondria and type 2 enzymes are present in endoplasmic reticulum (also known as microsomal fraction). Of the total 57 human P450 enzymes 50 are of microsomal variety and rely on electron transfer from the cofactor NADPH through a unique enzyme NADPH P450 oxidoreductase (also known as POR or CPR). The majority of drugs in clinical use are metabolized by a small number of P450 enzymes. Regulation of steroidogenesis in humans is carried out by four P450 enzymes: P450scc, P450C17, P450C21 and P450C19 (aromatase). All these enzymes except for P450scc are of microsomal, type 2 and require POR for activity. P450 enzymes have been studied extensively due to their role in drug and steroid metabolism and genetic variations in drug metabolizing P450s have been found to be responsible for altered drug responses. A genechip (Amplichip P450)(microarray) test to screen for variations in two of these P450s (2C19 and 2D6) had recently been approved for clinical use. We have shown that mutations in POR can cause endocrine dysfunctions like female infertility and severe cases of POR deficiency resemble a group of congenital disorder known as Antley-Bixler Syndrome. A recently completed population genetic variation study known as HapMap project as well as sequencing of POR by independent investigators have found several variations in the human POR gene. We have established functional studies of POR variants by testing the electron transfer to cytochrome c and another more specific test of the POR mediated 17-hydroxylation and 17,20 lyase activities of P450C17. Since all 50 microsomal P450 enzymes depend on POR for electron supply, we are putting forward the hypothesis that defects in POR could cause disorders in hepatic drug and xenobiotic metabolism as well as affect the functions of all steroid metabolizing microsomal P450 enzymes. Different P450 enzymes have variable affinities for POR and mutations / polymorphisms in POR could have different effect on different P450 enzymes. A change in activities of P450 by variant POR will lead to changes in effective/toxic dosages of drugs. In the past sequencing of P450 genes sometimes could not explain the reasons for defective drug/steroid metabolism. POR also supports heme degrading enzyme heme oxygenase and can reduce cytochrome b5, a component of many P450 mediated reactions. We plan to study the role of POR variations in human health and diseases. Findings from these studies will provide a better understanding of the endocrine disorders caused by POR variations and polymorphisms in human population and establish the pharmacogenomic role of POR variants in drug and steroid metabolism.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Ten novel mutations in the NR5A1 gene cause disordered sex development in 46,XY and ovarian insufficiency in 46,XX individuals.
Camats N, Pandey A V, Fernández-Cancio M, Andaluz P, Janner M, Torán N, Moreno F, Bereket A, Akcay T, García-García E, Muñoz M T, Gracia R, Nistal M, Castaño L, Mullis P E, Carrascosa A, Audí L, Flück C E (2012), Ten novel mutations in the NR5A1 gene cause disordered sex development in 46,XY and ovarian insufficiency in 46,XX individuals., in The Journal of clinical endocrinology and metabolism, 97(7), 1294-306.
A novel GH-1 gene mutation (GH-P59L) causes partial GH deficiency type II combined with bioinactive GH syndrome.
Petkovic Vibor, Eblé Andrée, Pandey Amit V, Betta Marta, Mella Patrizia, Flück Christa E, Buzi Fabio, Mullis Primus E (2011), A novel GH-1 gene mutation (GH-P59L) causes partial GH deficiency type II combined with bioinactive GH syndrome., in Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the Inte, 21(3), 160-6.
Characterization of novel StAR (steroidogenic acute regulatory protein) mutations causing non-classic lipoid adrenal hyperplasia.
Flück Christa E, Pandey Amit V, Dick Bernhard, Camats Núria, Fernández-Cancio Mónica, Clemente María, Gussinyé Miquel, Carrascosa Antonio, Mullis Primus E, Audi Laura (2011), Characterization of novel StAR (steroidogenic acute regulatory protein) mutations causing non-classic lipoid adrenal hyperplasia., in PloS one, 6(5), 20178-20178.
Clinical and biochemical consequences of p450 oxidoreductase deficiency.
Flück Christa E, Pandey Amit V (2011), Clinical and biochemical consequences of p450 oxidoreductase deficiency., in Endocrine development, 20, 63-79.
Deletion of P399_E401 in NADPH cytochrome P450 oxidoreductase results in partial mixed oxidase deficiency.
Flück Christa E, Mallet Delphine, Hofer Gaby, Samara-Boustani Dinane, Leger Juliane, Polak Michel, Morel Yves, Pandey Amit V (2011), Deletion of P399_E401 in NADPH cytochrome P450 oxidoreductase results in partial mixed oxidase deficiency., in Biochemical and biophysical research communications, 412(4), 572-7.
Loss of the C terminus of melanocortin receptor 2 (MC2R) results in impaired cell surface expression and ACTH insensitivity.
Hirsch Andrea, Meimaridou Eirini, Fernandez-Cancio Monica, Pandey Amit V, Clemente María, Audi Laura, Clark Adrian J L, Flück Christa E (2011), Loss of the C terminus of melanocortin receptor 2 (MC2R) results in impaired cell surface expression and ACTH insensitivity., in The Journal of clinical endocrinology and metabolism, 96(1), 65-72.
Molecular genetics and bioinformatics methods for diagnosis of endocrine disorders.
Pandey Amit V, Mullis PE (2011), Molecular genetics and bioinformatics methods for diagnosis of endocrine disorders., Karger Medical and Scientific Publishers, Basel, 32-52.
Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation.
Flück Christa E, Meyer-Böni Monika, Pandey Amit V, Kempná Petra, Miller Walter L, Schoenle Eugen J, Biason-Lauber Anna (2011), Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation., in American journal of human genetics, 89(2), 201-18.
Altered heme catabolism by heme oxygenase-1 caused by mutations in human NADPH cytochrome P450 reductase.
Pandey Amit V, Flück Christa E, Mullis Primus E (2010), Altered heme catabolism by heme oxygenase-1 caused by mutations in human NADPH cytochrome P450 reductase., in Biochemical and biophysical research communications, 400(3), 374-8.
Growth hormone (GH) deficiency type II: a novel GH-1 gene mutation (GH-R178H) affecting secretion and action.
Petkovic Vibor, Godi Michela, Pandey Amit V, Lochmatter Didier, Buchanan Charles R, Dattani Mehul T, Eblé Andrée, Flück Christa E, Mullis Primus E (2010), Growth hormone (GH) deficiency type II: a novel GH-1 gene mutation (GH-R178H) affecting secretion and action., in The Journal of clinical endocrinology and metabolism, 95(2), 731-9.
Reduction in hepatic drug metabolizing CYP3A4 activities caused by P450 oxidoreductase mutations identified in patients with disordered steroid metabolism.
Flück Christa E, Mullis Primus E, Pandey Amit V (2010), Reduction in hepatic drug metabolizing CYP3A4 activities caused by P450 oxidoreductase mutations identified in patients with disordered steroid metabolism., in Biochemical and biophysical research communications, 401(1), 149-53.
Restoration of mutant cytochrome P450 reductase activity by external flavin.
Nicolo Catherine, Flück Christa E, Mullis Primus E, Pandey Amit V (2010), Restoration of mutant cytochrome P450 reductase activity by external flavin., in Molecular and cellular endocrinology, 321(2), 245-52.
Modeling of human P450 oxidoreductase structure by in silico mutagenesis and MD simulation.
Flück Christa E, Mullis Primus E, Pandey Amit V (2009), Modeling of human P450 oxidoreductase structure by in silico mutagenesis and MD simulation., in Molecular and cellular endocrinology, 313(1-2), 17-22.
Nomenclature for alleles of the cytochrome P450 oxidoreductase gene.
Sim Sarah C, Miller Walter L, Zhong Xiao-Bo, Arlt Wiebke, Ogata Tsutomu, Ding Xinxin, Wolf C Roland, Flück Christa E, Pandey Amit V, Henderson Colin J, Porter Todd D, Daly Ann K, Nebert Daniel W, Ingelman-Sundberg Magnus (2009), Nomenclature for alleles of the cytochrome P450 oxidoreductase gene., in Pharmacogenetics and genomics, 19(7), 565-6.
P450 oxidoreductase deficiency - a new form of congenital adrenal hyperplasia.
Flück Christa E, Pandey Amit V, Huang Ningwu, Agrawal Vishal, Miller Walter L (2008), P450 oxidoreductase deficiency - a new form of congenital adrenal hyperplasia., in Endocrine development, 13, 67-81.
Clinical, structural and functional implications of mutations and polymorphisms in human NADPH P450 oxidoreductase.
Flück Christa E, Nicolo Catherine, Pandey Amit V (2007), Clinical, structural and functional implications of mutations and polymorphisms in human NADPH P450 oxidoreductase., in Fundamental & clinical pharmacology, 21(4), 399-410.
Modulation of human CYP19A1 activity by mutant NADPH P450 oxidoreductase.
Pandey Amit V, Kempná Petra, Hofer Gaby, Mullis Primus E, Flück Christa E (2007), Modulation of human CYP19A1 activity by mutant NADPH P450 oxidoreductase., in Molecular endocrinology, 21(10), 2579-2595.
The cytochrome P450 aromatase lacking exon 5 is associated with a phenotype of nonclassic aromatase deficiency and is also present in normal human steroidogenic tissues.
Pepe Carolina M, Saraco Nora I, Baquedano Maria Sonia, Guercio Gabriela, Vaiani Elisa, Marino Roxana, Pandey Amit V, Flück Christa E, Rivarola Marco A, Belgorosky Alicia (2007), The cytochrome P450 aromatase lacking exon 5 is associated with a phenotype of nonclassic aromatase deficiency and is also present in normal human steroidogenic tissues., in Clinical endocrinology, 67(5), 698-705.

Collaboration

Group / person Country
Types of collaboration
Prof. Walter L Miller, Department of Pediatrics, U of California San Francisco, United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Institute of Cellular Medicine, Newcastle University Medical School, Framlington Place, Newcastle u Great Britain and Northern Ireland (Europe)
- Publication
Hopital Robert Debre, Paris, France France (Europe)
- Publication
Hopital Necker-Enfants malades, Paris, France France (Europe)
- Publication
Wadsworth Center, New York State Department of Health, and School of Public Health, State Universit United States of America (North America)
- Publication
Dr. Anna Lauber, Pediatric Endocrinology and Diabetology, University Children’s Hospital Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Department of Endocrinology and Metabolism, National Research Institute for Child Health and Develo Japan (Asia)
- Publication
Prof. Yves Morel, Hospices Civils de Lyon, Bron, France France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Department of Environmental Health and Center for Environmental Genetics (CEG), University of Cinci United States of America (North America)
- Publication
Cancer Research UK Molecular Pharmacology Unit, Biomedical Research Institute, Ninewells Hospital an Great Britain and Northern Ireland (Europe)
- Publication
Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine, Un Great Britain and Northern Ireland (Europe)
- Publication
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky United States of America (North America)
- Publication
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kans United States of America (North America)
- Publication
Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden Sweden (Europe)
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Experimental Biology 2012 Talk given at a conference Clinical, biochemical and structural implications of mutations and polymorphisms in P450 oxidoreductase. 26.04.2012 San Diego, CA, USA, United States of America Pandey Amit V.;
17th International Conference on Cytochrome P450. Talk given at a conference Effect of POR mutations on steroid metabolism. 30.06.2011 Manchester, UK, Great Britain and Northern Ireland Pandey Amit V.;
Workshop on Protein Structure Individual talk Protein structure modelling. 16.06.2010 Dept of Chemistry, University of Bern, Switzerland Pandey Amit V.;
Servier Research Award Talk Individual talk Pharmacogenomics of p450 oxidoreductase. 02.12.2007 Kursal Bern, Switzerland Pandey Amit V.;
Lecture at Inst of Clinical Pharmacology, Bern Individual talk P450 oxidoreductase deficiency. 01.12.2007 IKP, Univ Bern, Switzerland Pandey Amit V.;


Awards

Title Year
Endocrine Society Travel Fellowship for 2009 meeting of Endocrine Society, USA 2009
Endocrine Trainee Award for 2009 Annual meeting of Endocrine Society, USA 2009
Swiss Society for Endocrinology Travel award 2009
FEBS Advance course young scientist award 2008
Theodor Kocher Prize 2008
EMBL PhD student event grant 2007
Servier Research Award 2007
Young Investigator Award, Swiss Society for Endocrinology 2007

Associated projects

Number Title Start Funding scheme
204518 Metabolic regulation by conformational changes in an electron transfer protein. 01.12.2021 Project funding (Div. I-III)
134926 Pathogenesis of disorders caused by human P450 oxidoreductase mutations 01.07.2012 Project funding (Div. I-III)

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