P450 oxidoreductase; POR; Steroid biosynthesis; disorders of sexual development; CYP3A4; CYP17A1; CYP19A1; CYP21A2; Heme oxygenase; Drug metabolism; Pharmacogenomics; Cytochrome P450
Jensen Simon Bo, Thodberg Sara, Parween Shaheena, Moses Matias E., Hansen Cecilie C., Thomsen Johannes, Sletfjerding Magnus B., Knudsen Camilla, Del Giudice Rita, Lund Philip M., Castaño Patricia R., Bustamante Yanet G., Velazquez Maria Natalia Rojas, Jørgensen Flemming Steen, Pandey Amit V., Laursen Tomas, Møller Birger Lindberg, Hatzakis Nikos S. (2021), Biased cytochrome P450-mediated metabolism via small-molecule ligands binding P450 oxidoreductase, in Nature Communications
, 12(1), 2260-2260.
Flück Christa E, Parween Shaheena, Rojas Velazquez Maria Natalia, Pandey Amit V (2020), Inhibition of placental CYP19A1 activity remains as a valid hypothesis for 46,XX virilization in P450 oxidoreductase deficiency., in Proceedings of the National Academy of Sciences of the United States of America
, 117(26), 14632-14633.
Parween Shaheena, Fernández-Cancio Mónica, Benito-Sanz Sara, Camats Núria, Rojas Velazquez Maria Natalia, López-Siguero Juan-Pedro, Udhane Sameer S, Kagawa Norio, Flück Christa E, Audí Laura, Pandey Amit V (2020), Molecular Basis of CYP19A1 Deficiency in a 46,XX Patient With R550W Mutation in POR: Expanding the PORD Phenotype., in The Journal of clinical endocrinology and metabolism
, 105(4), dgaa076.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Flück Christa E, Pandey Amit V (2015), P450 Oxidoreductase Deficiency (PORD), in New Maria I (ed.), Academic Press, New York, 125-143.
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.
Pandey Amit V, Sproll Patrick (2014), Pharmacogenomics of human P450 oxidoreductase., in Frontiers in pharmacology
, 5, 103-103.
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.
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.
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.
Flück Christa E, Pandey Amit V (2014), Steroidogenesis of the testis -- new genes and pathways., in Annales d'endocrinologie
, 75(2), 40-7.
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.
Pandey Amit V, Flück Christa E (2013), NADPH P450 oxidoreductase: structure, function, and pathology of diseases., in Pharmacology & therapeutics
, 138(2), 229-54.
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
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.
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.
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.
Zalewski Adam, Ma Nina S., Legeza Balazs, Renthal Nora, Flück Christa E., Pandey Amit V., 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.
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.