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Pathogenesis of disorders caused by human P450 oxidoreductase mutations

English title Pathogenesis of disorders caused by human P450 oxidoreductase mutations
Applicant Pandey Amit V.
Number 134926
Funding scheme Project funding (Div. I-III)
Research institution Universitäts-Kinderklinik Universität Bern
Institution of higher education University of Berne - BE
Main discipline Endocrinology
Start/End 01.07.2012 - 30.06.2016
Approved amount 331'000.00
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Keywords (12)

P450 oxidoreductase; POR; Steroid biosynthesis; disorders of sexual development; CYP3A4; CYP17A1; CYP19A1; CYP21A2; Heme oxygenase; Drug metabolism; Pharmacogenomics; Cytochrome P450

Lay Summary (English)

Lead
Lay summary


Pathogenesis of disorders caused by human P450 oxidoreductase mutations 

Patients with POR deficiency have disordered steroidogenesis due to malfunctioning of several key enzymes in the steroidogenesis pathway. Patients with genital abnormalities and an abnormal urinary steroid profile that suggested combined defects in CYP17A1 (17a-hydroxylase/17,20 lyase) and CYP21A2 (21-hydroxylase) were reported that suggested a role of POR, however, when the POR knockout was found to be embryonically lethal in mice POR was excluded as a candidate gene. Almost two decades later in a 2004 we reported (Flück et al, Nature Genetics, March 2004) the first four patients with mutations in POR gene. Subsequent studies confirmed the presence of POR mutations in patients with similar patterns of steroid abnormalities with and without ABS (Huang, Pandey et al. Am. J. Hum. Genetics 2005). In the patients of European descent the A287P mutation is most common; while Japanese patients often have the R457H mutation. 

Role of POR in steroid metabolism:

In the initial report the POR mutants A287P, R457H, V492E, C569Y and V608F were tested with 17a-hydroxylase and 17,20 lyase activities of CYP17A1.  A good correlation between the clinical features and the CYP17A1 activities was observed.   Later on we tested the effects of some POR variants on CYP19A1 (aromatase) activity. Mutations R457H and V492E located at FAD binding site of POR caused a complete loss of CYP19A1 activity, confirming that POR mutations disrupting the FAD binding and electron transfer will severely affect all P450s.
We have recently reported a novel POR mutation P399_E401del found in two unrelated Turkish families. The novel POR mutation P399_E401del had a clinical phenotype of ABS and DSD but only subclinical cortisol deficiency. In vitro functional testing of mutant POR P399_E401del on single enzymes showed a loss 68-85% activity for different P450s.

Diagnosis:

PORD can be diagnosed prenatally from the amniotic fluid or urine of the mother. The urine steroid profile of a mother carrying a fetus with PORD is characteristic for low levels of estriol but increased epiallopregnanediol disulfate (metabolite of pregnenolone), and increased androsterone and its precursor 17a-hydroxyallopregnanolone (5a reduced products coming from the alternative backdoor pathway leading to dihydrotestosterone production. The diagnosis of POR deficiency may be suggested from clinical and hormonal analysis but it requires molecular genetic analysis for confirmation and to know the specific defect as treatment may depend on severity of the effect on different interaction partners of POR.

 

Role in Drug metabolism:

We have found that POR mutants Y181D, A457H, Y459H, V492E and R616X lost more than 99% of drug metabolizing CYP3A4 activity, while 60-85% activity loss was observed for POR mutations A287P, C569Y and V608F [24]. Loss of CYP3A4 activity may result in increased risk of drug toxicities and adverse drug reactions in patients with severe POR mutations. Among non P450 partner proteins we have observed that POR mutants Y181D, A457H, Y459H, V492E and R616X result in total loss of heme oxygenase 1 (HO1) activity, while POR mutations A287P, C569Y and V608F lost 50-70% of HO1 activity

Therapeutic options:

Treatment may include replacement of glucocorticoids and sex steroids (and rarely mineralocorticoids) as assessed by low serum hormone levels. The skeletal malformations caused by POR deficiency require orthopedic management, and often reported mortality is due to skeletal abnormalities leading to respiratory problems (e.g. choanal obstruction). Computational docking studies and functional assays suggest that the activity loss of some POR variants may be rescued by flavin supplementation 
We were able to restore activities of POR Y181D and A287P which is not near the cofactor binding sites. However, which POR variant with what partner P450 may respond to external FMN, and whether flavin can be used as a treatment for affected patients remains to be tested.


References:

1. Flück CE, Tajima T, Pandey AV, Arlt W, Okuhara K, Verge CF, Jabs EW, Mendonca BB, Fujieda K and Miller WL. Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome. Nature Genetics 36: 228-30 (2004).


2. Pandey AV, Flück CE, Huang N, Tajima T, Fuijeda K and Miller WL. P450 oxidoreductase deficiency: a new disorder of steroidogenesis affecting all microsomal P450 enzymes. Endocrine Res 30: 881-888 (2004).

3. Huang N, Pandey AV, Agrawal V, Reardon W, Lapunzina PD, Mowatt D, Jabs EW, vanVliet G; Sack, J, Flück CE and Miller WL. Diversity and function of mutations in P450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis. Am. J. Hum. Genet. 76: 729-749 (2005).5. Pandey AV. Biochemical analysis of mutations in P450 oxidoreductase.  Biochem Soc Trans  34: 1186-1191 (2006).

4. Flück CE, Nicolo C & Pandey AV. Clinical structural and functional implications of mutations and polymorphisms in human NADPH P450 oxidoreductase. Fund. Clin. Pharmacol. 21: 399-410 (2007).6. Pandey AV, Kempna P, Hofer G, Mullis PE & Flück CE. Modulation of human CYP19A1 activity by mutant NADPH P450 oxidoreductase.  Mol Endocrinol 21: 2579-2595 (2007).16. Sim SC, Miller WL, Zhong XB, Arlt W, Ogata T, Ding X, Wolf CR, Flück CE, Pandey AV, Henderson CJ, Porter TD, Daly AK, Nebert DW, Ingelman-Sundberg M. Nomenclature for Alleles of the Cytochrome P450 Oxidoreductase (POR) Gene. Pharmacogenetics and Genomics 19: 565-566 (2009)

15. Flück CE, Mullis PE and Pandey AV. Modeling of human P450 oxidoreductase structure by In-silico mutagenesis and molecular dynamics simulations. Mol Cell Endocrinol 313: 17-22 (2009).

14. Fluck CE, Pandey AV, Huang N, Agrawal, V & Miller WL. P450 oxidoreductase deficiency – a new form of congenital adrenal hyperplasia.  Endocr Dev 13: 67-81 (2008)

13. Nicolo C, Flück CE, Mullis PE and Pandey AV. Restoration of mutant cytochrome P450 reductase activity by external flavin.  Mol Cell Endocrinol. 321: 245-252 (2010).

12. Pandey AV, Flück CE, Mullis PE. Altered heme catabolism by heme oxygenase-1 caused by mutations in human NADPH cytochrome P450 reductase. Biochem. Biophys. Res. Commun 400: 374-378 (2010).

11. Flück CE, Mullis PE and Pandey AV. Reduction in hepatic drug metabolizing CYP3A4 activities caused by P450 oxidoreductase mutations identified in patients with disordered steroid metabolism. Biochem. Biophys. Res. Commun 401: 149-153 (2010).

10. Flück CE and Pandey AV. Clinical and biochemical consequences of P450 oxidoreductase deficiency. Endo. Dev. 20: 63-79 (2011).

9. Flück CE, Pandey AV, Dick B, Camats N, Fernandez-Cancio M, Celmente M, Gussinye M, Carrascosa A, Mullis PE and Audi L. Characterization of novel StAR (Steroidogenic Acute Regulatory Protein) mutations causing non-classic lipoid adrenal hyperplasia. PLoS One 6(5):e20178 (2011).

8. Flück CE, Mallet D, Hofer G, Samara-Boustani D, Leger J, Polak M, Morel Y and Pandey AV. Biochem. Biophys. Res. Commun 412: 572-577 (2011).

7. Flück CE, Meyer-Böni M, Pandey AV, Kempná P, Miller WL, Schoenle EJ, and Biason-Lauber A. Why Boys will be Boys: Two Pathways of Fetal Testicular Androgen Biosynthesis Are Needed for Male Sexual Differentiation. Am J. Hum Genetics 89:201-218 (2011). 
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Variability in human drug metabolizing cytochrome P450 CYP2C9, CYP2C19 and CYP3A5 activities caused by genetic variations in cytochrome P450 oxidoreductase
Velazquez Maria Natalia Rojas, Parween Shaheena, Udhane Sameer S., Pandey Amit V. (2019), Variability in human drug metabolizing cytochrome P450 CYP2C9, CYP2C19 and CYP3A5 activities caused by genetic variations in cytochrome P450 oxidoreductase, in Biochemical and Biophysical Research Communications, 515(1), 133-138.
Role of Protein-Protein Interactions in Metabolism: Genetics, Structure, function
Pandey Amit V, Henderson Colin J, Ishii Yuji, Kranendonk Michel, Backes Wayne L, Zanger Ullrich M (2018), Role of Protein-Protein Interactions in Metabolism: Genetics, Structure, function, Frontiers Media SA, Lausanne.
Editorial: Role of Protein-Protein Interactions in Metabolism: Genetics, Structure, Function
Pandey Amit V., Henderson Colin J., Ishii Yuji, Kranendonk Michel, Backes Wayne L., Zanger Ulrich M. (2017), Editorial: Role of Protein-Protein Interactions in Metabolism: Genetics, Structure, Function, in Frontiers in Pharmacology, 8, 881.
CYP17A1 inhibitor abiraterone, an anti-prostate cancer drug, also inhibits the 21-hydroxylase activity of CYP21A2
Malikova Jana, Brixius-Anderko Simone, Udhane Sameer S., Parween Shaheena, Dick Bernhard, Bernhardt Rita, Pandey Amit V. (2017), CYP17A1 inhibitor abiraterone, an anti-prostate cancer drug, also inhibits the 21-hydroxylase activity of CYP21A2, in The Journal of Steroid Biochemistry and Molecular Biology, 174, 192-200.
Altered CYP19A1 and CYP3A4 Activities Due to Mutations A115V, T142A, Q153R and P284L in the Human P450 Oxidoreductase
Udhane Sameer S, Parween Shaheena, Kagawa Norio, Pandey Amit V (2017), Altered CYP19A1 and CYP3A4 Activities Due to Mutations A115V, T142A, Q153R and P284L in the Human P450 Oxidoreductase, in Front. Pharmacol, 8, 580.
Altered CYP19A1 and CYP3A4 Activities Due to Mutations A115V, T142A, Q153R and P284L in the Human P450 Oxidoreductase.
Udhane Sameer S, Parween Shaheena, Kagawa Norio, Pandey Amit V (2017), Altered CYP19A1 and CYP3A4 Activities Due to Mutations A115V, T142A, Q153R and P284L in the Human P450 Oxidoreductase., in Front Pharmacol., 8, 580.
Vitamin D-dependent rickets type 1 caused by mutations in CYP27B1 affecting protein interactions with adrenodoxin
Zalewski Adam, Ma Nina S., Legeza Balazs, Renthal Nora, Flück Christa E., Pandey Amit V. (2016), Vitamin D-dependent rickets type 1 caused by mutations in CYP27B1 affecting protein interactions with adrenodoxin, in The Journal of Clinical Endocrinology & Metabolism, 101(9), 3409-3418.
Specificity of anti-prostate cancer CYP17A1 inhibitors on androgen biosynthesis
Udhane Sameer S., Dick Bernhard, Hu Qingzhong, Hartmann Rolf W., Pandey Amit V. (2016), Specificity of anti-prostate cancer CYP17A1 inhibitors on androgen biosynthesis, in Biochemical and Biophysical Research Communications, 477(4), 1005-1010.
Impact on CYP19A1 activity by mutations in NADPH cytochrome P450 oxidoreductase.
Flück Christa E, Pandey Amit V (2016), Impact on CYP19A1 activity by mutations in NADPH cytochrome P450 oxidoreductase., in The Journal of steroid biochemistry and molecular biology, 165, 64-70.
P450 Oxidoreductase deficiency: Analysis of mutations and polymorphisms.
Burkhard Fabian Z, Parween Shaheena, Udhane Sameer S, Flück Christa E, Pandey Amit V (2016), P450 Oxidoreductase deficiency: Analysis of mutations and polymorphisms., in The Journal of steroid biochemistry and molecular biology, 165, 38-50.
P450 Oxidoreductase Deficiency (PORD)
Flück Christa E, Pandey Amit V (2015), P450 Oxidoreductase Deficiency (PORD), in New Maria I (ed.), Academic Press, New York, 125-143.
Altered Drug and Steroid Metabolism by Mutations in Human NADPH Cytochrome P450 Reductase
Pandey Amit V, Fluck CE (2015), Altered Drug and Steroid Metabolism by Mutations in Human NADPH Cytochrome P450 Reductase, in The FASEB Journal, 29(1), LB522.
Pharmacogenomics of human P450 oxidoreductase.
Pandey Amit V, Sproll Patrick (2014), Pharmacogenomics of human P450 oxidoreductase., in Frontiers in pharmacology, 5, 103-103.
NADPH-cytochrome P450 oxidoreductase: roles in physiology, pharmacology, and toxicology.
Riddick David S, Ding Xinxin, Wolf C Roland, Porter Todd D, Pandey Amit V, Zhang Qing-Yu, Gu Jun, Finn Robert D, Ronseaux Sebastien, McLaughlin Lesley A, Henderson Colin J, Zou Ling, Flück Christa E (2014), NADPH-cytochrome P450 oxidoreductase: roles in physiology, pharmacology, and toxicology., in Drug metabolism and disposition: the biological fate of chemicals, 41(1), 12-23.
Of marsupials and men: "Backdoor" dihydrotestosterone synthesis in male sexual differentiation.
Biason-Lauber Anna, Miller Walter L, Pandey Amit V, Flück Christa E (2014), Of marsupials and men: "Backdoor" dihydrotestosterone synthesis in male sexual differentiation., in Molecular and cellular endocrinology, 371(1-2), 124-32.
Characterization of a novel CYP19A1 (aromatase) R192H mutation causing virilization of a 46,XX newborn, undervirilization of the 46,XY brother, but no virilization of the mother during pregnancies.
Bouchoucha Nadia, Samara-Boustani Dinane, Pandey Amit V, Bony-Trifunovic Helene, Hofer Gaby, Aigrain Yves, Polak Michel, Flück Christa E (2014), Characterization of a novel CYP19A1 (aromatase) R192H mutation causing virilization of a 46,XX newborn, undervirilization of the 46,XY brother, but no virilization of the mother during pregnancies., in Molecular and cellular endocrinology, 390(1-2), 8-17.
Steroidogenesis of the testis -- new genes and pathways.
Flück Christa E, Pandey Amit V (2014), Steroidogenesis of the testis -- new genes and pathways., in Annales d'endocrinologie, 75(2), 40-7.
Marsupial Pathway in Humans.
Biason-Lauber A, Pandey Amit V, Miller Walter L, Flück Christa E (2014), Marsupial Pathway in Humans., in New Maria I (ed.), Academic Press, New York, 215-224.
NADPH P450 oxidoreductase: structure, function, and pathology of diseases.
Pandey Amit V, Flück Christa E (2013), NADPH P450 oxidoreductase: structure, function, and pathology of diseases., in Pharmacology & therapeutics, 138(2), 229-54.
P450 Oxidoreductase Deficiency: loss of activity caused by protein instability from a novel L374H mutation
Parween Shaheena, Boulez Florence Roucher, Flück Christa E., Lienhardt-Roussie Anne, Mallet Delphine, Morel Yves, Pandey Amit V., P450 Oxidoreductase Deficiency: loss of activity caused by protein instability from a novel L374H mutation, in The Journal of Clinical Endocrinology & Metabolism, jc.2016-1928-jc.2016-1928.
Retinoic acid receptor beta and angiopoietin-like protein 1 are involved in the regulation of human androgen biosynthesis.
Udhane Sameer S, Pandey Amit V, Hofer Gaby, Mullis Primus E, Flück Christa E, Retinoic acid receptor beta and angiopoietin-like protein 1 are involved in the regulation of human androgen biosynthesis., in Scientific reports, 5, 10132-10132.
STAR splicing mutations cause the severe phenotype of lipoid congenital adrenal hyperplasia: insights from a novel splice mutation and review of reported cases.
Camats Núria, Pandey Amit V, Fernández-Cancio Mónica, Fernández Juan M, Ortega Ana M, Udhane Sameer, Andaluz Pilar, Audí Laura, Flück Christa E, STAR splicing mutations cause the severe phenotype of lipoid congenital adrenal hyperplasia: insights from a novel splice mutation and review of reported cases., in Clinical endocrinology, 80(2), 191-9.
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, 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.

Collaboration

Group / person Country
Types of collaboration
Christa E Flück Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Nikos Hatzakis, Center for Synthetic Biology, University of Copenhagen, Denmark Denmark (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
University Hospital Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Yves Morel France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Walter L. Miller, University of California San Francisco United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Yasara Biosciences / Dr. Elmar Krieger Austria (Europe)
- Industry/business/other use-inspired collaboration
Baylor College of Medicine, Houston United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Laura Audi Spain (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
BIOCEV DAYS Talk given at a conference Regulation of Salt, Sugar and Sex Steroids in Humans by Genetic Variations in Cytochrome P450 Oxidoreductase (POR). 17.06.2019 BIOCEV, Průmyslová 595, 252 50 Vestec, Czech Republic, Czech Republic Pandey Amit V.;
18th Adrenal Cortex Conference Talk given at a conference Genotype/phenotype correlations of POR mutations 26.06.2018 Munich, Germany Pandey Amit V.;
'Functional Biology and Molecular Interactions Talk given at a conference Regulation of Salt, Sugar and Sex Steroids in Humans by Genetic Variations in Cytochrome P450 Oxidoreductase 20.12.2017 Lucknow, India Pandey Amit V.;
20th International Conference on Cytochrome P450 Poster Altered steroid and drug metabolism by a P450 oxidoreductase variant found in apparently normal population 27.08.2017 Düsseldorf, Germany Parween Shaheena; Pandey Amit V.;
20th International Conference on Cytochrome P450 Talk given at a conference Androgen biosynthesis in humans by cytochrome P450s: Regulation, and targeting in diseases. 27.08.2017 Düsseldorf, Germany Pandey Amit V.;
6th I-DSD Symposia Talk given at a conference Bioinformatics analysis of DSD genes 29.06.2017 Copengagen, Denmark Pandey Amit V.;
Seminars in Steroid Metabolism Individual talk P450 redox partner variations in human population and their role in metabolism. 05.05.2017 Saarbruecken, DE, Germany Pandey Amit V.;
ASPET 2017 Annual Meeting at Experimental Biology 2017 Talk given at a conference Altered CYP19A1 and CYP3A4 Activities Due to Mutations in the Flavin Mononucleotide Binding Domain of Human P450 Oxidoreductase 22.04.2017 Chicago, IL, United States of America Pandey Amit V.;
56 Annual meeting of the European Society of Pediatric Endocrinology Talk given at a conference Characterization of P450 mutations affecting protein interactions. 07.09.2016 Paris, France Pandey Amit V.;
Seminars in Steroid Metabolism Talk given at a conference P450 oxidoreductase deficiency. 22.04.2016 Universitaet Saarland, Germany Pandey Amit V.;
54th Annual Meeting of the European Society for Paediatric Endocrinology. Talk given at a conference Effect of CYP17A1 inhibitors orteronel & galeterone on adrenal androgen biosynthesis. 01.10.2015 Barcelona, Spain Udhane Sameer; Pandey Amit V.;
54th Annual Meeting of the European Society for Paediatric Endocrinology Talk given at a conference Effect of P450 Oxidoreductase Variants on Metabolism by Cytochrome P450 Proteins. 01.10.2015 Barcelona, Spain Pandey Amit V.; Parween Shaheena; Udhane Sameer;
19th International Conference on Cytochrome P450, Tokyo, Japan Poster Effect of CYP17A1 inhibitors orteronel and galeterone on adrenal androgen biosynthesis 12.06.2015 Tokyo, Japan Pandey Amit V.; Udhane Sameer;
19th International Conference on Cytochrome P450, Tokyo, Japan Poster Conformational studies of CYP27B1 variants in complex with adrenodoxin: insights into a delicate binding/unbinding balance. 12.06.2015 Tokyo, Japan Pandey Amit V.;
19th International Conference on Cytochrome P450, Tokyo, Japan Talk given at a conference Interactions of Cytochrome P450 Reductase (POR) and Cytochrome b5 with P450 : Impact on Sex, Drugs and Metabolic Disorders 12.06.2015 Tokyo, Japan Pandey Amit V.;
19th International Conference on Cytochrome P450, Tokyo, Japan Poster EFFECT OF P450 OXIDOREDUCTASE VARIANTS ON METABOLISM, ELECTRON TRANSFER AND INTERACTIONS WITH P450 12.06.2015 Tokyo, Japan Parween Shaheena; Udhane Sameer; Pandey Amit V.;
Experimental Biology meeting 2015 Poster Altered Drug and Steroid Metabolism by Mutations in Human NADPH Cytochrome P450 Reductase 28.03.2015 Boston, MA, USA, United States of America Pandey Amit V.;
Talk at University of Copenhagen Individual talk Effect of mutations and polymorphisms in human cytochrome P450 reductase 26.03.2015 Copenhagen, Denmark, Denmark Pandey Amit V.;
Talk at University of Cincinnati Medical Center Individual talk Disorder of steroid metabolism by variations in cytochrome P450 genes and their interaction partners. 06.03.2015 Cincinnati, Ohio, United States of America Pandey Amit V.;
57th KLOTZ Endocrinology meeting Talk given at a conference Steroidogenesis of testes: New genes and pathways 05.06.2014 FACULTE COCHIN 24 rue du Faubourg Saint Jacques 75014 PARIS, France Pandey Amit V.;
20th International Symposium on Microsomes and Drug Oxidations Talk given at a conference Impact of P450 reductase variations on drug and steroid metabolism in humans 18.05.2014 Stuttgart, Germany Pandey Amit V.;
UKC Seminar in Lab Medicine Individual talk P450 reductase variants and their role in metabolism. 07.05.2014 Bern, Switzerland, Switzerland Pandey Amit V.;
18th International Conference on Cytochrome P450 Talk given at a conference Human Disorders of Steroidogenic P450s 18.06.2013 Seattle, United States of America Pandey Amit V.;
Seventh ESPE Advanced Seminar in Developmental Endocrinology Talk given at a conference Bioinformatic tools for steroid research 30.05.2013 Bern, Switzerland Pandey Amit V.;
Talk at Toxicology program at Biozentrum Basel Individual talk Pharmacogenomics of P450 oxidoreductase 18.03.2013 Basel, Switzerland Pandey Amit V.;
50th Anniversary Symposium on Cytochrome P450 Poster Clinical, structural and functional implications of mutations and polymorphisms in human NADPH-cytochrome P450 oxidoreductase 01.12.2012 Fukuoka, Japan Pandey Amit V.;
The 50th Anniversary Symposium on Cytochrome P450 Poster Selectivity of CYP17A1 Activities Revealed by a Mutation Causing 17,20 Lyase Deficiency. 01.12.2012 Fukuoka, Japan, Japan Pandey Amit V.;
Talk at University of California San Francisco Individual talk Regulation of steroid hormone biosynthesis in humans. 19.10.2012 San Francisco, United States of America Pandey Amit V.;


Communication with the public

Communication Title Media Place Year
New media (web, blogs, podcasts, news feeds etc.) A new approach to the treatment of prostate cancer Health Europa International 2018
New media (web, blogs, podcasts, news feeds etc.) Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiratero Urotoday.com International 2018
New media (web, blogs, podcasts, news feeds etc.) Neuer Ansatz im Kampf gegen Prostatakrebs infoticker.ch German-speaking Switzerland International 2018
Media relations: print media, online media Neuer Ansatz im Kampf gegen Prostatakrebs entdeckt Laborscope International German-speaking Switzerland 2018
New media (web, blogs, podcasts, news feeds etc.) New Drug target to combat prostate cancer Uni Bern News International German-speaking Switzerland 2018
New media (web, blogs, podcasts, news feeds etc.) Nytt läkemedelsmål för att bekämpa prostatacancer Medicine Consultant International 2018

Awards

Title Year
Travel award for ESPE 2018 2018
Travel Grant for ASPET / Experimental Biology 2017
Postdoc Fellowship of SNSF 2016
Travel Grant from Swiss society for Endocrinology and Diabetology 2015
Travel Grant from Swiss society for Endocrinology and Diabetology 2015

Associated projects

Number Title Start Funding scheme
113719 Pharmacogenomics of human P450 oxidoreductase 01.07.2007 Project funding (Div. I-III)

Abstract

Summary: Pathogenesis of disorders caused by human P450 oxidoreductase mutationsBACKGROUND: Mutations in human NADPH cytochrome P450 oxidoreductase (POR, CPR, CYPOR) cause congenital adrenal hyperplasia (Flück, Tajima et al. 2004). All Microsomal P450s involved in steroid/drug metabolism need POR for electron transfer from NADPH, therefore it was suggested that POR mutations are unlikely (Miller 1986). Patients with apparent combination of defects in enzymatic activities of CYP17A1 and CYP21A2 revealed no mutations and the underlying defects remained unclear. In 2004 we and others reported the first POR mutations in patients who seemed to have steroid abnormalities suggesting combined defects in CYP17A1 and CYP21A2 (Flück, Tajima et al. 2004). Subsequent studies confirmed the presence of POR mutations in patients with similar patterns of steroid abnormalities. An official nomenclature of POR mutations was established and is listed on the P450 alleles website (www.cypalleles.ki.se/por.htm) (Sim, Miller et al. 2009).HYPOTHESIS: Subjects with partial POR deficiency may have PCOS-like phenotype and drug intolerance syndromes or problems in heme catabolism. Therefore, identification of the specificity of POR variations in such groups of patients is important. As several different POR mutations give rise to endocrine disorders, our aim is to characterize these differences by advanced biochemical studies. A major goal is to understand the differences in CYP17A1 and CYP19A1 (aromatase) activities affected by specific POR variants. Our recent results with 5 POR mutants showed differences in activities with CYP17A1, CYP19A1 as well as CYP3A4. Characterization of POR mutations with specific target proteins will explain the causes of pathogenesis at molecular level and aid in diagnosis at earlier stage. SPECIFIC AIMS: (1) Identification of POR mutants with specific effects with focus on CYP19A1 (aromatase). (2) Effect of specific POR variations on drug metabolizing P450s focusing on the disease associated POR variant A287P predominantly found in European patients with POR deficiency. (3) Advanced studies on mutations in FMN and NADPH binding domain to understand specificity of POR mutation affecting different partner proteins and testing supplementation with external FMN to restore activity for formulating a treatment strategy in POR deficient patients. Test this treatment (vitamin B supplementation) in affected patients. (4) Improving structure-function relationship and diagnostics.SIGNIFICANCE: These studies will establish pathophyosiology of P450 reductase mutations in drug and steroid metabolism, and help with supplements /dose adjustment in POR deficiency. As we were able restore some POR mutants by extra flavin (vitamin B), this line of investigation is extremely important & may be a treatment option to partially reduce the impact of POR deficiency (at least for some mutations) by simply supplementing vitamin B to affected subjects.
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