NADPH P450 oxidoreductase: Structure, function, and pathology of diseases

Pharmacology and Therapeutics

Volumn 138, Issue 2, 2013, Pages 229-254

  Pandey, Amit V ^a   Flück, Christa E ^a  

^a UNIVERSITY OF BERN   (Switzerland)

Author keywords

Antley Bixler syndrome; CYP17A1; CYP3A4; Cytochrome P450; P450 oxidoreductase; POR

Indexed keywords

ANDROSTANOLONE; CODEINE; CORTICOTROPIN; CYCLOSPORIN A; CYTOCHROME B5; CYTOCHROME C; CYTOCHROME P450; CYTOCHROME P450 1A2; CYTOCHROME P450 2C19; CYTOCHROME P450 2C9; CYTOCHROME P450 3A4; CYTOCHROME P450 REDUCTASE; DIAZEPAM; ERYTHROMYCIN; FERRICYANIDE; FLAVINE ADENINE NUCLEOTIDE; FLAVINE MONONUCLEOTIDE; FLUCONAZOLE; FLUOXETINE; HEME OXYGENASE; MIDAZOLAM; PARACETAMOL; QUINIDINE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE FERRIHEMOPROTEIN REDUCTASE; RIFAMPICIN; RITONAVIR; TESTOSTERONE; VERAPAMIL;

AMINO ACID SEQUENCE; AMINO TERMINAL SEQUENCE; AMNION FLUID ANALYSIS; BONE MALFORMATION; CLINICAL FEATURE; CROSS LINKING; DRUG METABOLISM; ELECTRON TRANSPORT; ENZYME ACTIVITY; ENZYME ANALYSIS; ENZYME CONFORMATION; ENZYME MECHANISM; ENZYME METABOLISM; ENZYME POLYMORPHISM; ENZYME STRUCTURE; GENE MUTATION; GENETIC ASSOCIATION; GENETIC VARIABILITY; GENOTYPE PHENOTYPE CORRELATION; HUMAN; IMMUNOASSAY; KARYOTYPE 46,XX; KARYOTYPE 46,XY; METABOLOME; MISSENSE MUTATION; NONHUMAN; NUCLEOTIDE SEQUENCE; OXIDATION REDUCTION REACTION; P450 OXIDOREDUCTASE DEFICIENCY; PATHOLOGY; PRIORITY JOURNAL; PROTEIN PROCESSING; PROTEIN PROTEIN INTERACTION; REVIEW; SEXUAL DEVELOPMENT; SITE DIRECTED MUTAGENESIS; SKELETON MALFORMATION; STEROIDOGENESIS;

AMINO ACID SEQUENCE; ANIMALS; ANTLEY-BIXLER SYNDROME PHENOTYPE; BINDING SITES; HUMANS; MODELS, MOLECULAR; MOLECULAR SEQUENCE DATA; MUSCULOSKELETAL ABNORMALITIES; MUTATION; NADPH-FERRIHEMOPROTEIN REDUCTASE; PHARMACEUTICAL PREPARATIONS; POLYMORPHISM, GENETIC; PROTEIN CONFORMATION; XENOBIOTICS;

EID: 84875217200     PISSN: 01637258     EISSN: 1879016X     Source Type: Journal    
DOI: 10.1016/j.pharmthera.2013.01.010     Document Type: Review

References (237)

1. M. Adachi, K. Tachibana, Y. Asakura, T. Yamamoto, K. Hanaki, and A. Oka Compound heterozygous mutations of cytochrome P450 oxidoreductase gene (POR) in two patients with Antley-Bixler syndrome Am J Med Genet 128A 2004 333 339
2. V. Agrawal, J.H. Choi, K.M. Giacomini, and W.L. Miller Substrate-specific modulation of CYP3A4 activity by genetic variants of cytochrome P450 oxidoreductase Pharmacogenet Genomics 20 2010 611 618
3. V. Agrawal, N. Huang, and W.L. Miller Pharmacogenetics of P450 oxidoreductase: effect of sequence variants on activities of CYP1A2 and CYP2C19 Pharmacogenet Genomics 18 2008 569 576
4. A. Aguilar, S. Wu, and F. De Luca P450 oxidoreductase expressed in rat chondrocytes modulates chondrogenesis via cholesterol- and Indian Hedgehog-dependent mechanisms Endocrinology 150 2009 2732 2739
5. L. Aigrain, F. Fatemi, O. Frances, E. Lescop, and G. Truan Dynamic control of electron transfers in diflavin reductases Int J Mol Sci 13 2012 15012 15041
6. L. Aigrain, D. Pompon, S. Morera, and G. Truan Structure of the open conformation of a functional chimeric NADPH cytochrome P450 reductase EMBO Rep 10 2009 742 747
7. K.A. Aleck, and D.L. Bartley Multiple malformation syndrome following fluconazole use in pregnancy: report of an additional patient Am J Med Genet 72 1997 253 256
8. R. Antley, and D. Bixler Trapezoidocephaly, midfacial hypoplasia and cartilage abnormalities with multiple synostoses and skeletal fractures Birth Defects Orig Artic Ser 11 1975 397 401
9. W. Arlt, E.A. Walker, N. Draper, H.E. Ivison, J.P. Ride, and F. Hammer Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study Lancet 363 2004 2128 2135
10. R.J. Auchus The backdoor pathway to dihydrotestosterone Trends Endocrinol Metab 15 2004 432 438
11. R.J. Auchus, T.C. Lee, and W.L. Miller Cytochrome b5 augments the 17,20-lyase activity of human P450c17 without direct electron transfer J Biol Chem 273 1998 3158 3165
12. R.J. Auchus, and W.L. Miller Molecular modeling of human P450c17 (17a-hydroxylase/17,20-lyase): insights into reaction mechanisms and effects of mutations Mol Endocrinol 13 1999 1169 1182
13. W.L. Backes, and R.W. Kelley Organization of multiple cytochrome P450s with NADPH-cytochrome P450 reductase in membranes Pharmacol Ther 98 2003 221 233
14. A. Bartoszek Metabolic activation of adriamycin by NADPH-cytochrome P450 reductase; overview of its biological and biochemical effects Acta Biochim Pol 49 2002 323 331
15. A. Bartoszek, and C.R. Wolf Enhancement of doxorubicin toxicity following activation by NADPH cytochrome P450 reductase Biochem Pharmacol 43 1992 1449 1457
16. R. Bernhardt, A. Makower, G.R. Janig, and K. Ruckpaul Selective chemical modification of a functionally linked lysine in cytochrome P-450 LM2 Biochim Biophys Acta 785 1984 186 190
17. R. Bernhardt, H. Stiel, and K. Ruckpaul Distance between lysine 384 and heme of cytochrome P-450 LM2 (P-450 IIB4) studied by fluorescence energy transfer measurements Biochem Biophys Res Commun 163 1989 1282 1289
18. H.F. Bligh, A. Bartoszek, C.N. Robson, I.D. Hickson, C.B. Kasper, and J.D. Beggs Activation of mitomycin C by NADPH:cytochrome P-450 reductase Cancer Res 50 1990 7789 7792
19. D.S. Bredt, P.M. Hwang, C.E. Glatt, C. Lowenstein, R.R. Reed, and S.H. Snyder Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase Nature 351 1991 714 718
20. E. Bullock, and J.H. Sequeira The relation of the suprarenal capsules to the sexual organs Trans Pathol Soc London 56 1905 189 208
21. N.N. Bumpus, and P.F. Hollenberg Cross-linking of human cytochrome P450 2B6 to NADPH-cytochrome P450 reductase: identification of a potential site of interaction J Inorg Biochem 104 2010 485 488
22. G.C. Butler, and G.F. Marrian The isolation of pregnane-3,17,20-triol from the urine of women showing the adrenogenital syndrome J Biol Chem 119 1937 565 570
23. N. Camats, A.V. Pandey, M. Fernandez-Cancio, P. Andaluz, M. Janner, and N. Toran Ten novel mutations in the NR5A1 gene cause disordered sex development in 46,XY and ovarian insufficiency in 46,XX individuals J Clin Endocrinol Metab 97 2012 E1294 E1306
24. X. Chen, L.Q. Pan, H. Naranmandura, S. Zeng, and S.Q. Chen Influence of various polymorphic variants of cytochrome P450 oxidoreductase (POR) on drug metabolic activity of CYP3A4 and CYP2B6 PLoS One 7 2012 e38495
25. K. Chun, J. Siegel-Bartelt, D. Chitayat, J. Phillips, and P.N. Ray FGFR2 mutation associated with clinical manifestations consistent with Antley-Bixler syndrome Am J Med Genet 77 1998 219 224
26. B.S. Cohen, and R.W. Estabrook Microsomal electron transport reactions. I. Interaction of reduced triphosphopyridine nucleotide during the oxidative demethylation of aminopyrine and cytochrome b 5 reduction Arch Biochem Biophys 143 1971 37 45
27. M.M. Cohen Jr. The new bone biology: pathologic, molecular, and clinical correlates Am J Med Genet A 140 2006 2646 2706
28. G. Crisponi, C. Porcu, and M.E. Piu Antley-Bixler syndrome: case report and review of the literature Clin Dysmorphol 6 1997 61 68
29. J. D'Agostino, X. Ding, P. Zhang, K. Jia, C. Fang, and Y. Zhu Potential biological functions of cytochrome P450 reductase-dependent enzymes in small intestine: novel link to expression of major histocompatibility complex class II genes J Biol Chem 287 2012 17777 17788
30. A. Das, and S.G. Sligar Modulation of the cytochrome P450 reductase redox potential by the phospholipid bilayer Biochemistry 48 2009 12104 12112
31. D.R. Davydov, A.A. Kariakin, N.A. Petushkova, and J.A. Peterson Association of cytochromes P450 with their reductases: opposite sign of the electrostatic interactions in P450BM-3 as compared with the microsomal 2B4 system Biochemistry 39 2000 6489 6497
32. D.R. Davydov, T.V. Knyushko, I.P. Kanaeva, Y.M. Koen, N.F. Samenkova, and A.I. Archakov Interactions of cytochrome P450 2B4 with NADPH-cytochrome P450 reductase studied by fluorescent probe Biochimie 78 1996 734 743
33. L. De Crecchio Giuseppe Marzo: Sopra un caso di apparenze virili in una donna Morgagni 7 1865 154
34. H. de Jonge, C. Metalidis, M. Naesens, D. Lambrechts, and D.R. Kuypers The P450 oxidoreductase*28 SNP is associated with low initial tacrolimus exposure and increased dose requirements in CYP3A5-expressing renal recipients Pharmacogenomics 12 2011 1281 1291
35. N. Debeljak, M. Fink, and D. Rozman Many facets of mammalian lanosterol 14a-demethylase from the evolutionarily conserved cytochrome P450 family CYP51 Arch Biochem Biophys 409 2003 159 171
36. S. Deller, S. Sollner, R. Trenker-El-Toukhy, I. Jelesarov, G.M. Gubitz, and P. Macheroux Characterization of a thermostable NADPH:FMN oxidoreductase from the mesophilic bacterium Bacillus subtilis Biochemistry 45 2006 7083 7091
37. C.D. DeLozier, R.M. Antley, R. Williams, N. Green, R.M. Heller, and D. Bixler The syndrome of multisynostotic osteodysgenesis with long-bone fractures Am J Med Genet 7 1980 391 403
38. V. Dhir, H.E. Ivison, N. Krone, C.H. Shackleton, A.J. Doherty, and P.M. Stewart Differential inhibition of CYP17A1 and CYP21A2 activities by the P450 oxidoreductase mutant A287P Mol Endocrinol 21 2007 1958 1968
39. E.A. Dierks, S.C. Davis, and P.R. Ortiz de Montellano Glu-320 and Asp-323 are determinants of the CYP4A1 hydroxylation regiospecificity and resistance to inactivation by 1-aminobenzotriazole Biochemistry 37 1998 1839 1847
40. M. Dobrinas, J. Cornuz, L. Pedrido, and C.B. Eap Influence of cytochrome P450 oxidoreductase genetic polymorphisms on CYP1A2 activity and inducibility by smoking Pharmacogenet Genomics 22 2012 143 151
41. G.K. Dresser, J.D. Spence, and D.G. Bailey Pharmacokinetic- pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition Clin Pharmacokinet 38 2000 41 57
42. J. Ellis, A. Gutierrez, I.L. Barsukov, W.C. Huang, J.G. Grossmann, and G.C. Roberts Domain motion in cytochrome P450 reductase: conformational equilibria revealed by NMR and small-angle X-ray scattering J Biol Chem 284 2009 36628 36637
43. H.G. Enoch, and P. Strittmatter Cytochrome b5 reduction by NADPH-cytochrome P-450 reductase J Biol Chem 254 1979 8976 8981
44. R.W. Estabrook, M.R. Franklin, B. Cohen, A. Shigamatzu, and A.G. Hildebrandt Biochemical and genetic factors influencing drug metabolism. Influence of hepatic microsomal mixed function oxidation reactions on cellular metabolic control Metabolism 20 1971 187 199
45. R.W. Estabrook, M.S. Shet, C.W. Fisher, C.M. Jenkins, and M.R. Waterman The interaction of NADPH-P450 reductase with P450: an electrochemical study of the role of the flavin mononucleotide-binding domain Arch Biochem Biophys 333 1996 308 315
46. Y. Farooq, and G.C. Roberts Kinetics of electron transfer between NADPH-cytochrome P450 reductase and cytochrome P450 3A4 Biochem J 432 2010 485 493
47. A. Ferreira, I. Marguti, I. Bechmann, V. Jeney, A. Chora, and N.R. Palha Sickle hemoglobin confers tolerance to Plasmodium infection Cell 145 2011 398 409
48. D. Fishelovitch, S. Shaik, H.J. Wolfson, and R. Nussinov How does the reductase help to regulate the catalytic cycle of cytochrome P450 3A4 using the conserved water channel? J Phys Chem B 114 2010 5964 5970
49. C.W. Fisher, M.S. Shet, and R.W. Estabrook Construction of plasmids and expression in Escherichia coli of enzymatically active fusion proteins containing the heme-domain of a P450 linked to NADPH-P450 reductase Methods Enzymol 272 1996 15 25
50. C.E. Flück, D. Mallet, G. Hofer, D. Samara-Boustani, J. Leger, and M. Polak Deletion of P399-E401 in NADPH cytochrome P450 oxidoreductase results in partial mixed oxidase deficiency Biochem Biophys Res Commun 412 2011 572 577
51. C.E. Flück, M. Meyer-Böni, A.V. Pandey, P. Kempna, W.L. Miller, and E.J. Schoenle Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation Am J Hum Genet 89 2011 201 218
52. C.E. Flück, and W.L. Miller GATA-4 and GATA-6 modulate tissue-specific transcription of the human gene for P450c17 by direct interaction with Sp1 Mol Endocrinol 18 2004 1144 1157
53. C.E. Flück, P.E. Mullis, and A.V. Pandey Modeling of human P450 oxidoreductase structure by in silico mutagenesis and MD simulation Mol Cell Endocrinol 313 2009 17 22
54. C.E. Flück, P.E. Mullis, and A.V. Pandey Reduction in hepatic drug metabolizing CYP3A4 activities caused by P450 oxidoreductase mutations identified in patients with disordered steroid metabolism Biochem Biophys Res Commun 401 2010 149 153
55. C.E. Flück, C. Nicolo, and A.V. Pandey Clinical, structural and functional implications of mutations and polymorphisms in human NADPH P450 oxidoreductase Fundam Clin Pharmacol 21 2007 399 410
56. C.E. Flück, and A.V. Pandey Clinical and biochemical consequences of P450 oxidoreductase deficiency Endocr Dev 20 2011 63 79
57. C.E. Flück, A.V. Pandey, B. Dick, N. Camats, M. Fernandez-Cancio, and M. Clemente Characterization of novel StAR (steroidogenic acute regulatory protein) mutations causing non-classic lipoid adrenal hyperplasia PLoS One 6 2011 e20178
58. C.E. Flück, A.V. Pandey, N. Huang, V. Agrawal, and W.L. Miller P450 oxidoreductase deficiency - a new form of congenital adrenal hyperplasia Endocr Dev 13 2008 67 81
59. C.E. Flück, T. Tajima, A.V. Pandey, W. Arlt, K. Okuhara, and C.F. Verge Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome Nat Genet 36 2004 228 230
60. M. Fukami, T. Hasegawa, R. Horikawa, T. Ohashi, G. Nishimura, and K. Homma Cytochrome P450 oxidoreductase deficiency in three patients initially regarded as having 21-hydroxylase deficiency and/or aromatase deficiency: diagnostic value of urine steroid hormone analysis Pediatr Res 59 2006 276 280
61. M. Fukami, K. Homma, T. Hasegawa, and T. Ogata Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development Dev Dyn 2012 10.1002/dvdy.23892
62. M. Fukami, R. Horikawa, T. Nagai, T. Tanaka, Y. Naiki, and N. Sato Cytochrome P450 oxidoreductase gene mutations and Antley-Bixler syndrome with abnormal genitalia and/or impaired steroidogenesis: molecular and clinical studies in 10 patients J Clin Endocrinol Metab 90 2005 414 426
63. M. Fukami, T. Nagai, H. Mochizuki, K. Muroya, G. Yamada, and K. Takitani Anorectal and urinary anomalies and aberrant retinoic acid metabolism in cytochrome P450 oxidoreductase deficiency Mol Genet Metab 100 2010 269 273
64. M. Fukami, G. Nishimura, K. Homma, T. Nagai, K. Hanaki, and A. Uematsu Cytochrome P450 oxidoreductase deficiency: identification and characterization of biallelic mutations and genotype-phenotype correlations in 35 Japanese patients J Clin Endocrinol Metab 94 2009 1723 1731
65. F. Gofflot, C. Hars, F. Illien, F. Chevy, C. Wolf, and J.J. Picard Molecular mechanisms underlying limb anomalies associated with cholesterol deficiency during gestation: implications of Hedgehog signaling Hum Mol Genet 12 2003 1187 1198
66. A.M. Gomes, S. Winter, K. Klein, M. Turpeinen, E. Schaeffeler, and M. Schwab Pharmacogenomics of human liver cytochrome P450 oxidoreductase: multifactorial analysis and impact on microsomal drug oxidation Pharmacogenomics 10 2009 579 599
67. K.W. Gripp, C.A. Stolle, D.M. McDonald-McGinn, R.I. Markowitz, S.P. Bartlett, and J.A. Katowitz Phenotype of the fibroblast growth factor receptor 2 Ser351Cys mutation: Pfeiffer syndrome type III Am J Med Genet 78 1998 356 360
68. J. Gu, Y. Weng, Q.Y. Zhang, H. Cui, M. Behr, and L. Wu Liver-specific deletion of the NADPH-cytochrome P450 reductase gene: impact on plasma cholesterol homeostasis and the function and regulation of microsomal cytochrome P450 and heme oxygenase J Biol Chem 278 2003 25895 25901
69. F.P. Guengerich Destruction of heme and hemoproteins mediated by liver microsomal reduced nicotinamide adenine dinucleotide phosphate-cytochrome P-450 reductase Biochemistry 17 1978 3633 3639
70. F.P. Guengerich Reduction of cytochrome b5 by NADPH-cytochrome P450 reductase Arch Biochem Biophys 440 2005 204 211
71. F.P. Guengerich, and W.W. Johnson Kinetics of ferric cytochrome P450 reduction by NADPH-cytochrome P450 reductase: rapid reduction in the absence of substrate and variations among cytochrome P450 systems Biochemistry 36 1997 14741 14750
72. A. Gutierrez, A.W. Munro, A. Grunau, C.R. Wolf, N.S. Scrutton, and G.C. Roberts Interflavin electron transfer in human cytochrome P450 reductase is enhanced by coenzyme binding. Relaxation kinetic studies with coenzyme analogues Eur J Biochem 270 2003 2612 2621
73. D. Hamdane, C. Xia, S.C. Im, H. Zhang, J.J. Kim, and L. Waskell Structure and function of an NADPH-cytochrome P450 oxidoreductase in an open conformation capable of reducing cytochrome P450 J Biol Chem 284 2009 11374 11384
74. M. Haniu, T. Iyanagi, K. Legesse, and J.E. Shively Structural analysis of NADPH-cytochrome P-450 reductase from porcine hepatic microsomes. Sequences of proteolytic fragments, cysteine-containing peptides, and a NADPH-protected cysteine peptide J Biol Chem 259 1984 13703 13711
75. M. Haniu, M.E. McManus, D.J. Birkett, T.D. Lee, and J.E. Shively Structural and functional analysis of NADPH-cytochrome P-450 reductase from human liver: complete sequence of human enzyme and NADPH-binding sites Biochemistry 28 1989 8639 8645
76. I. Hanukoglu, and T. Gutfinger cDNA sequence of adrenodoxin reductase. Identification of NADP-binding sites in oxidoreductases Eur J Biochem 180 1989 479 484
77. S.N. Hart, S. Wang, K. Nakamoto, C. Wesselman, Y. Li, and X.B. Zhong Genetic polymorphisms in cytochrome P450 oxidoreductase influence microsomal P450-catalyzed drug metabolism Pharmacogenet Genomics 18 2008 11 24
78. C.A. Hasemann, R.G. Kurumbail, S.S. Boddupalli, J.A. Peterson, and J. Deisenhofer Structure and function of cytochromes P450: a comparative analysis of three crystal structures Structure 3 1995 41 62
79. S. Hassell, and M.G. Butler Antley-Bixler syndrome: report of a patient and review of literature Clin Genet 46 1994 372 376
80. P.S. Hench, E.C. Kendall, C.H. Slocum, and H.F. Polley The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone; compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis Mayo Clin Proc 24 1949 181 197
81. C.J. Henderson, D.M. Otto, D. Carrie, M.A. Magnuson, A.W. McLaren, and I. Rosewell Inactivation of the hepatic cytochrome P450 system by conditional deletion of hepatic cytochrome P450 reductase J Biol Chem 278 2003 13480 13486
82. C.J. Henderson, G.J. Pass, and C.R. Wolf The hepatic cytochrome P450 reductase null mouse as a tool to identify a successful candidate entity Toxicol Lett 162 2006 111 117
83. Y. Higashimoto, H. Sakamoto, S. Hayashi, M. Sugishima, K. Fukuyama, and G. Palmer Involvement of NADPH in the interaction between heme oxygenase-1 and cytochrome P450 reductase J Biol Chem 280 2005 729 737
84. A. Hildebrandt, and R.W. Estabrook Evidence for the participation of cytochrome b 5 in hepatic microsomal mixed-function oxidation reactions Arch Biochem Biophys 143 1971 66 79
85. K. Homma, T. Hasegawa, T. Nagai, M. Adachi, R. Horikawa, and I. Fujiwara Urine steroid hormone profile analysis in cytochrome P450 oxidoreductase deficiency: implication for the backdoor pathway to dihydrotestosterone J Clin Endocrinol Metab 91 2006 2643 2649
86. B.L. Horecker Triphosphate nucleotide-cytochrome c reductase in liver J Biol Chem 183 1950 593 605
87. B.L. Horecker, and L.A. Heppel The reduction of cytochrome c by xanthine oxidase J Biol Chem 178 1949 683 690
88. N. Huang, V. Agrawal, K.M. Giacomini, and W.L. Miller Genetics of P450 oxidoreductase: sequence variation in 842 individuals of four ethnicities and activities of 15 missense mutations Proc Natl Acad Sci U S A 105 2008 1733 1738
89. N. Huang, A.V. Pandey, V. Agrawal, W. Reardon, P.D. Lapunzina, and D. Mowat Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis Am J Hum Genet 76 2005 729 749
90. P.A. Hubbard, A.L. Shen, R. Paschke, C.B. Kasper, and J.J. Kim NADPH-cytochrome P450 oxidoreductase. Structural basis for hydride and electron transfer J Biol Chem 276 2001 29163 29170
91. J. Idkowiak, E.M. Malunowicz, V. Dhir, N. Reisch, M. Szarras-Czapnik, and D.M. Holmes Concomitant mutations in the P450 oxidoreductase and androgen receptor genes presenting with 46, XY disordered sex development and androgenization at adrenarche J Clin Endocrinol Metab 95 2010 3418 3427
92. J. Idkowiak, S. O'Riordan, N. Reisch, E.M. Malunowicz, F. Collins, and M.N. Kerstens Pubertal presentation in seven patients with congenital adrenal hyperplasia due to P450 oxidoreductase deficiency J Clin Endocrinol Metab 96 2011 E453 E462
93. T. Iyanagi Structure and function of NADPH-cytochrome P450 reductase and nitric oxide synthase reductase domain Biochem Biophys Res Commun 338 2005 520 528
94. T. Iyanagi, and H.S. Mason Some properties of hepatic reduced nicotinamide adenine dinucleotide phosphate-cytochrome c reductase Biochemistry 12 1973 2297 2308
95. T. Iyanagi, C. Xia, and J.J. Kim NADPH-cytochrome P450 oxidoreductase: prototypic member of the diflavin reductase family Arch Biochem Biophys 528 2012 72 89
96. H.H. Jang, A.P. Jamakhandi, S.Z. Sullivan, C.H. Yun, P.F. Hollenberg, and G.P. Miller Beta sheet 2-alpha helix C loop of cytochrome P450 reductase serves as a docking site for redox partners Biochim Biophys Acta 1804 2010 1285 1293
97. M. Janner, A.V. Pandey, P.E. Mullis, and C.E. Flück Clinical and biochemical description of a novel CYP21A2 gene mutation 962-963insA using a new 3D model for the P450c21 protein Eur J Endocrinol 155 2006 143 151
98. M. Jenner, J. Ellis, W.C. Huang, E. Lloyd Raven, G.C. Roberts, and N.J. Oldham Detection of a protein conformational equilibrium by electrospray ionisation-ion mobility-mass spectrometry Angew Chem Int Ed Engl 50 2011 8291 8294
99. P.A. Karplus, M.J. Daniels, and J.R. Herriott Atomic structure of ferredoxin-NADP+ reductase: prototype for a structurally novel flavoenzyme family Science 251 1991 60 66
100. R.I. Kelley, L.E. Kratz, R.L. Glaser, M.L. Netzloff, L.M. Wolf, and E.W. Jabs Abnormal sterol metabolism in a patient with Antley-Bixler syndrome and ambiguous genitalia Am J Med Genet 110 2002 95 102
101. J.M. Ko, C.K. Cheon, G.H. Kim, and H.W. Yoo A case of Antley-Bixler syndrome caused by compound heterozygous mutations of the cytochrome P450 oxidoreductase gene Eur J Pediatr 168 2009 877 880
102. Y. Koyama, K. Homma, M. Fukami, M. Miwa, K. Ikeda, and T. Ogata Two-step biochemical differential diagnosis of classic 21-hydroxylase deficiency and cytochrome P450 oxidoreductase deficiency in Japanese infants by GC-MS measurement of urinary pregnanetriolone/tetrahydroxycortisone ratio and 11beta-hydroxyandrosterone Clin Chem 58 2012 741 747
103. L. Kragie, S.D. Turner, C.J. Patten, C.L. Crespi, and D.M. Stresser Assessing pregnancy risks of azole antifungals using a high throughput aromatase inhibition assay Endocr Res 28 2002 129 140
104. M. Kranendonk, C.C. Marohnic, S.P. Panda, M.P. Duarte, J.S. Oliveira, and B.S. Masters Impairment of human CYP1A2-mediated xenobiotic metabolism by Antley-Bixler syndrome variants of cytochrome P450 oxidoreductase Arch Biochem Biophys 475 2008 93 99
105. N. Krone, B.A. Hughes, G.G. Lavery, P.M. Stewart, W. Arlt, and C.H. Shackleton Gas chromatography/mass spectrometry (GC/MS) remains a pre-eminent discovery tool in clinical steroid investigations even in the era of fast liquid chromatography tandem mass spectrometry (LC/MS/MS) J Steroid Biochem Mol Biol 121 2010 496 504
106. N. Krone, N. Reisch, J. Idkowiak, V. Dhir, H.E. Ivison, and B.A. Hughes Genotype-phenotype analysis in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency J Clin Endocrinol Metab 97 2012 E257 E267
107. D.C. Lamb, Y. Kim, L.V. Yermalitskaya, V.N. Yermalitsky, G.I. Lepesheva, and S.L. Kelly A second FMN binding site in yeast NADPH-cytochrome P450 reductase suggests a mechanism of electron transfer by diflavin reductases Structure 14 2006 51 61
108. R. Larsen, R. Gozzelino, V. Jeney, L. Tokaji, F.A. Bozza, and A.M. Japiassu A central role for free heme in the pathogenesis of severe sepsis Sci Transl Med 2 2010 51ra71
109. K. Laue, H.M. Pogoda, P.B. Daniel, A. van Haeringen, Y. Alanay, and S. von Ameln Craniosynostosis and multiple skeletal anomalies in humans and zebrafish result from a defect in the localized degradation of retinoic acid Am J Hum Genet 89 2011 595 606
110. G.S. Lee, D.M. Kochhar, and M.D. Collins Retinoid-induced limb malformations Curr Pharm Des 10 2004 2657 2699
111. A.P. Li, D.L. Kaminski, and A. Rasmussen Substrates of human hepatic cytochrome P450 3A4 Toxicology 104 1995 1 8
112. L. Li, and T.D. Porter Chlorzoxazone hydroxylation in microsomes and hepatocytes from cytochrome P450 oxidoreductase-null mice J Biochem Mol Toxicol 23 2009 357 363
113. A.Y. Lu, K.W. Junk, and M.J. Coon Resolution of the cytochrome P-450-containing w-hydroxylation system of liver microsomes into three components J Biol Chem 244 1969 3714 3721
114. A. Makower, R. Bernhardt, H. Rabe, G.R. Janig, and K. Ruckpaul Identification of lysine (384) in cytochrome P-450 LM2 as functionally linked residue Biomed Biochim Acta 43 1984 1333 1341
115. C.C. Marohnic, W.J. Huber Iii, J. Patrick Connick, J.R. Reed, K. McCammon, and S.P. Panda Mutations of human cytochrome P450 reductase differentially modulate heme oxygenase-1 activity and oligomerization Arch Biochem Biophys 513 2011 42 50
116. C.C. Marohnic, S.P. Panda, K. McCammon, J. Rueff, B.S. Masters, and M. Kranendonk Human cytochrome P450 oxidoreductase deficiency caused by the Y181D mutation: molecular consequences and rescue of defect Drug Metab Dispos 38 2010 332 340
117. B.S. Masters The journey from NADPH-cytochrome P450 oxidoreductase to nitric oxide synthases Biochem Biophys Res Commun 338 2005 507 519
118. B.S. Masters, and B.A. Schacter The catalysis of heme degradation by purified NADPH-cytochrome C reductase in the absence of other microsomal proteins Ann Clin Res 8 Suppl. 17 1976 18 27
119. T. Matsubara, J. Baron, L.L. Peterson, and J.A. Peterson NADPH-cytochrome P450 reductase Arch Biochem Biophys 172 1976 463 469
120. W.L. Miller Congenital adrenal hyperplasia N Engl J Med 314 1986 1321 1322
121. W.L. Miller Minireview: regulation of steroidogenesis by electron transfer Endocrinology 146 2005 2544 2550
122. W.L. Miller, V. Agrawal, D. Sandee, M.K. Tee, N. Huang, and J.H. Choi Consequences of POR mutations and polymorphisms Mol Cell Endocrinol 336 2011 174 179
123. W.L. Miller, and R.J. Auchus The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders Endocr Rev 32 2011 81 151
124. W.L. Miller, N. Huang, V. Agrawal, and K.M. Giacomini Genetic variation in human P450 oxidoreductase Mol Cell Endocrinol 300 2009 180 184
125. W.L. Miller, N. Huang, C.E. Flück, and A.V. Pandey P450 oxidoreductase deficiency Lancet 364 2004 1663
126. V. Mokashi, L. Li, and T.D. Porter Cytochrome b5 reductase and cytochrome b5 support the CYP2E1-mediated activation of nitrosamines in a recombinant Ames test Arch Biochem Biophys 412 2003 147 152
127. D. Moutinho, C.C. Marohnic, S.P. Panda, J. Rueff, B.S. Masters, and M. Kranendonk Altered human CYP3A4 activity caused by Antley-Bixler syndrome-related variants of NADPH-cytochrome P450 oxidoreductase measured in a robust in vitro system Drug Metab Dispos 40 2012 754 760
128. M. Muenke, U. Schell, A. Hehr, N.H. Robin, H.W. Losken, and A. Schinzel A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome Nat Genet 8 1994 269 274
129. A.W. Munro, M.A. Noble, L. Robledo, S.N. Daff, and S.K. Chapman Determination of the redox properties of human NADPH-cytochrome P450 reductase Biochemistry 40 2001 1956 1963
130. M.B. Murataliev, R. Feyereisen, and F.A. Walker Electron transfer by diflavin reductases Biochim Biophys Acta (BBA) Proteins Proteomics 1698 2004 1 26
131. S.G. Nadler, and H.W. Strobel Role of electrostatic interactions in the reaction of NADPH-cytochrome P-450 reductase with cytochromes P-450 Arch Biochem Biophys 261 1988 418 429
132. S.G. Nadler, and H.W. Strobel Identification and characterization of an NADPH-cytochrome P450 reductase derived peptide involved in binding to cytochrome P450 Arch Biochem Biophys 290 1991 277 284
133. M. Nagao, T. Ishibashi, T. Okayasu, and Y. Imai Possible involvement of NADPH-cytochrome P450 reductase and cytochrome b5 on beta-ketostearoyl-CoA reduction in microsomal fatty acid chain elongation supported by NADPH FEBS Lett 155 1983 11 14
134. R. Narayanasami, P.M. Horowitz, and B.S. Masters Flavin-binding and protein structural integrity studies on NADPH-cytochrome P450 reductase are consistent with the presence of distinct domains Arch Biochem Biophys 316 1995 267 274
135. D.W. Nebert Microsomal cytochromes b5 and P450 during induction of aryl hydrocarbon hydroxylase activity in mammalian cell culture J Biol Chem 245 1970 519 527
136. C. Nicolo, C.E. Flück, P.E. Mullis, and A.V. Pandey Restoration of mutant cytochrome P450 reductase activity by external flavin Mol Cell Endocrinol 321 2010 245 252
137. L. Nikfarjam, S. Izumi, T. Yamazaki, and S. Kominami The interaction of cytochrome P450 17alpha with NADPH-cytochrome P450 reductase, investigated using chemical modification and MALDI-TOF mass spectrometry Biochim Biophys Acta 1764 2006 1126 1131
138. H. Nishino, and T. Ishibashi Evidence for requirement of NADPH-cytochrome P450 oxidoreductase in the microsomal NADPH-sterol Delta7-reductase system Arch Biochem Biophys 374 2000 293 298
139. Y. Nisimoto Localization of cytochrome c-binding domain on NADPH-cytochrome P-450 reductase J Biol Chem 261 1986 14232 14239
140. T. Niwa, K. Minami, and M. Katagiri Effect of histidine-tag and R457H and E580Q mutations on catalytic activity of recombinant human cytochrome P450 oxidoreductase Drug Metab Pharmacokinet 27 2012 150 154
141. T. Omura, and R. Sato A new cytochrome in liver microsomes J Biol Chem 237 1962 1375 1376
142. B. Oneda, S. Crettol, E. Jaquenoud Sirot, M. Bochud, N. Ansermot, and C.B. Eap The P450 oxidoreductase genotype is associated with CYP3A activity in vivo as measured by the midazolam phenotyping test Pharmacogenet Genomics 19 2009 877 883
143. T. Ono, and K. Bloch Solubilization and partial characterization of rat liver squalene epoxidase J Biol Chem 250 1975 1571 1579
144. M. Onoda, and P.F. Hall Cytochrome b5 stimulates purified testicular microsomal cytochrome P-450 (C21 side-chain cleavage) Biochem Biophys Res Commun 108 1982 454 460
145. D.M. Otto, C.J. Henderson, D. Carrie, M. Davey, T.E. Gundersen, and R. Blomhoff Identification of novel roles of the cytochrome P450 system in early embryogenesis: effects on vasculogenesis and retinoic acid homeostasis Mol Cell Biol 23 2003 6103 6116
146. A. Pamplona, A. Ferreira, J. Balla, V. Jeney, G. Balla, and S. Epiphanio Heme oxygenase-1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria Nat Med 13 2007 703 710
147. A.V. Pandey, C.E. Flück, N. Huang, T. Tajima, K. Fujieda, and W.L. Miller P450 oxidoreductase deficiency: a new disorder of steroidogenesis affecting all microsomal P450 enzymes Endocr Res 30 2004 881 888
148. A.V. Pandey, C.E. Flück, and P.E. Mullis Altered heme catabolism by heme oxygenase-1 caused by mutations in human NADPH cytochrome P450 reductase Biochem Biophys Res Commun 400 2010 374 378
149. A.V. Pandey, P. Kempna, G. Hofer, P.E. Mullis, and C.E. Flück Modulation of human CYP19A1 activity by mutant NADPH P450 oxidoreductase Mol Endocrinol 21 2007 2579 2595
150. A.V. Pandey, S.H. Mellon, and W.L. Miller Protein phosphatase 2A and phosphoprotein SET regulate androgen production by P450c17 J Biol Chem 278 2003 2837 2844
151. A.V. Pandey, and W.L. Miller Regulation of 17,20 lyase activity by cytochrome b5 and by serine phosphorylation of P450c17 J Biol Chem 280 2005 13265 13271
152. A.V. Pandey, B.L. Tekwani, and V.C. Pandey Characterization of hemozoin from liver and spleen of mice infected with Plasmodium yoelli, a rodent malaria parasite Biomed Res-Tokyo 16 1995 115 120
153. A.V. Pandey, P. Srivastava, B.L. Tekwani, and V.C. Pandey Effect of Plasmodium yoelii infection on constitutive and phenobarbitone inducible mixed function oxidase system of mice J Parasit Dis 20 1996 141 144
154. W.J. Park, G.A. Meyers, X. Li, C. Theda, D. Day, and S.J. Orlow Novel FGFR2 mutations in Crouzon and Jackson-Weiss syndromes show allelic heterogeneity and phenotypic variability Hum Mol Genet 4 1995 1229 1233
155. R.E. Peterson, J. Imperato-McGinley, T. Gautier, and C.H.L. Shackleton Male pseudohermaphroditism due to multiple defects in steroid-biosynthetic microsomal mixed-function oxidases. A new variant of congenital adrenal hyperplasia N Engl J Med 313 1985 1182 1191
156. A.H. Phillips, and R.G. Langdon Hepatic triphosphopyridine nucleotide-cytochrome c reductase: isolation, characterization, and kinetic studies J Biol Chem 237 1962 2652 2660
157. S.R. Polusani, R. Kar, M.A. Riquelme, B.S. Masters, and S.P. Panda Regulation of gap junction function and Connexin 43 expression by cytochrome P450 oxidoreductase (CYPOR) Biochem Biophys Res Commun 411 2011 490 495
158. D. Pompon, B. Louerat, A. Bronine, and P. Urban Yeast expression of animal and plant P450s in optimized redox environments Methods Enzymol 272 1996 51 64
159. D. Pompon, A. Perret, A. Bellamine, R. Laine, J.C. Gautier, and P. Urban Genetically engineered yeast cells and their applications Toxicol Lett 82-83 1995 815 822
160. T.D. Porter The roles of cytochrome b5 in cytochrome P450 reactions J Biochem Mol Toxicol 16 2002 311 316
161. T.D. Porter, S. Banerjee, E.I. Stolarczyk, and L. Zou Suppression of cytochrome P450 reductase (POR) expression in hepatoma cells replicates the hepatic lipidosis observed in hepatic POR-null mice Drug Metab Dispos 39 2011 966 973
162. T.D. Porter, T.W. Beck, and C.B. Kasper NADPH-cytochrome P-450 oxidoreductase gene organization correlates with structural domains of the protein Biochemistry 29 1990 9814 9818
163. T.D. Porter, and C.B. Kasper Coding nucleotide sequence of rat NADPH-cytochrome P-450 oxidoreductase cDNA and identification of flavin-binding domains Proc Natl Acad Sci U S A 82 1985 973 977
164. T.D. Porter, and C.B. Kasper NADPH-cytochrome P-450 oxidoreductase: flavin mononucleotide and flavin adenine dinucleotide domains evolved from different flavoproteins Biochemistry 25 1986 1682 1687
165. S. Praporski, S.M. Ng, A.D. Nguyen, C.J. Corbin, A. Mechler, and J. Zheng Organization of cytochrome P450 enzymes involved in sex steroid synthesis: protein-protein interactions in lipid membranes J Biol Chem 284 2009 33224 33232
166. L.J. Pulleyn, W. Reardon, D. Wilkes, P. Rutland, B.M. Jones, and R. Hayward Spectrum of craniosynostosis phenotypes associated with novel mutations at the fibroblast growth factor receptor 2 locus Eur J Hum Genet 4 1996 283 291
167. T.J. Pursley, I.K. Blomquist, J. Abraham, H.F. Andersen, and J.A. Bartley Fluconazole-induced congenital anomalies in three infants Clin Infect Dis 22 1996 336 340
168. S. Ramji, C. Lee, T. Inaba, A.V. Patterson, and D.S. Riddick Human NADPH-cytochrome p450 reductase overexpression does not enhance the aerobic cytotoxicity of doxorubicin in human breast cancer cell lines Cancer Res 63 2003 6914 6919
169. I. Raw, and H.R. Mahler Studies of electron transport enzymes. III. Cytochrome b5 of pig liver mitochondria J Biol Chem 234 1959 1867 1873
170. W. Reardon, A. Smith, J.W. Honour, P. Hindmarsh, D. Das, and G. Rumsby Evidence for digenic inheritance in some cases of Antley-Bixler syndrome? J Med Genet 37 2000 26 32
171. W. Reardon, R.M. Winter, P. Rutland, L.J. Pulleyn, B.M. Jones, and S. Malcolm Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome Nat Genet 8 1994 98 103
172. V. Ribes, D.M. Otto, L. Dickmann, K. Schmidt, B. Schuhbaur, and C. Henderson Rescue of cytochrome P450 oxidoreductase (Por) mouse mutants reveals functions in vasculogenesis, brain and limb patterning linked to retinoic acid homeostasis Dev Biol 303 2007 66 81
173. D.S. Riddick, X. Ding, C.R. Wolf, T.D. Porter, A.V. Pandey, and Q.Y. Zhang NADPH-cytochrome P450 oxidoreductase: roles in physiology, pharmacology, and toxicology Drug Metab Dispos 41 2013 12 23
174. L.J. Roman, J. McLain, and B.S.S. Masters Chimeric enzymes of cytochrome P450 oxidoreductase and neuronal nitric-oxide synthase reductase domain reveal structural and functional differences J Biol Chem 278 2003 25700 25707
175. P. Rutland, L.J. Pulleyn, W. Reardon, M. Baraitser, R. Hayward, and B. Jones Identical mutations in the FGFR2 gene cause both Pfeiffer and Crouzon syndrome phenotypes Nat Genet 9 1995 173 176
176. T. Sahakitrungruang, N. Huang, M.K. Tee, V. Agrawal, W.E. Russell, and P. Crock Clinical, genetic, and enzymatic characterization of P450 oxidoreductase deficiency in four patients J Clin Endocrinol Metab 94 2009 4992 5000
177. Y. Saito, N. Yamamoto, N. Katori, K. Maekawa, H. Fukushima-Uesaka, and D. Sugimoto Genetic polymorphisms and haplotypes of por, encoding cytochrome p450 oxidoreductase, in a Japanese population Drug Metab Pharmacokinet 26 2011 107 116
178. D. Sandee, K. Morrissey, V. Agrawal, H.K. Tam, M.A. Kramer, and T.S. Tracy Effects of genetic variants of human P450 oxidoreductase on catalysis by CYP2D6 in vitro Pharmacogenet Genomics 20 2010 677 686
179. B.A. Schacter, E.B. Nelson, H.S. Marver, and B.S. Masters Immunochemical evidence for an association of heme oxygenase with the microsomal electron transport system J Biol Chem 247 1972 3601 3607
180. F. Schaefer, C. Anderson, B. Can, and B. Say Novel mutation in the FGFR2 gene at the same codon as the Crouzon syndrome mutations in a severe Pfeiffer syndrome type 2 case Am J Med Genet 75 1998 252 255
181. W.H. Schaefer, T.M. Harris, and F.P. Guengerich Characterization of the enzymatic and nonenzymatic peroxidative degradation of iron porphyrins and cytochrome P-450 heme Biochemistry 24 1985 3254 3263
182. K. Schmidt, C. Hughes, J.A. Chudek, S.R. Goodyear, R.M. Aspden, and R. Talbot Cholesterol metabolism: the main pathway acting downstream of cytochrome P450 oxidoreductase in skeletal development of the limb Mol Cell Biol 29 2009 2716 2729
183. R.R. Scott, L.G. Gomes, N. Huang, G. Van Vliet, and W.L. Miller Apparent manifesting heterozygosity in P450 oxidoreductase deficiency and its effect on coexisting 21-hydroxylase deficiency J Clin Endocrinol Metab 92 2007 2318 2322
184. N.S. Scrutton, A. Berry, and R.N. Perham Redesign of the coenzyme specificity of a dehydrogenase by protein engineering Nature 343 1990 38 43
185. C. Shackleton, J. Marcos, W. Arlt, and B.P. Hauffa Prenatal diagnosis of P450 oxidoreductase deficiency (ORD): a disorder causing low pregnancy estriol, maternal and fetal virilization, and the Antley-Bixler syndrome phenotype Am J Med Genet 129A 2004 105 112
186. C.H.L. Shackleton Role of a disordered steroid metabolome in the elucidation of sterol and steroid biosynthesis Lipids 47 2012 1 12
187. A.L. Shen, M.J. Christensen, and C.B. Kasper NADPH-cytochrome P-450 oxidoreductase. The role of cysteine 566 in catalysis and cofactor binding J Biol Chem 266 1991 19976 19980
188. A.L. Shen, and C.B. Kasper Role of acidic residues in the interaction of NADPH-cytochrome P450 oxidoreductase with cytochrome P450 and cytochrome c J Biol Chem 270 1995 27475 27480
189. A.L. Shen, and C.B. Kasper Role of Ser457 of NADPH-cytochrome P450 oxidoreductase in catalysis and control of FAD oxidation-reduction potential Biochemistry 35 1996 9451 9459
190. A.L. Shen, and C.B. Kasper Differential contributions of NADPH-cytochrome P450 oxidoreductase FAD binding site residues to flavin binding and catalysis J Biol Chem 275 2000 41087 41091
191. A.L. Shen, K.A. O'Leary, and C.B. Kasper Association of multiple developmental defects and embryonic lethality with loss of microsomal NADPH-cytochrome P450 oxidoreductase J Biol Chem 277 2002 6536 6541
192. A.L. Shen, T.D. Porter, T.E. Wilson, and C.B. Kasper Structural analysis of the FMN binding domain of NADPH-cytochrome P-450 oxidoreductase by site-directed mutagenesis J Biol Chem 264 1989 7584 7589
193. A.L. Shen, D.S. Sem, and C.B. Kasper Mechanistic studies on the reductive half-reaction of NADPH-cytochrome P450 oxidoreductase J Biol Chem 274 1999 5391 5398
194. S. Shen, and H.W. Strobel The role of cytochrome P450 lysine residues in the interaction between cytochrome P450IA1 and NADPH-cytochrome P450 reductase Arch Biochem Biophys 294 1992 83 90
195. S. Shen, and H.W. Strobel Role of lysine and arginine residues of cytochrome P450 in the interaction between cytochrome P4502B1 and NADPH-cytochrome P450 reductase Arch Biochem Biophys 304 1993 257 265
196. E.A. Shephard, C.N. Palmer, H.J. Segall, and I.R. Phillips Quantification of cytochrome P450 reductase gene expression in human tissues Arch Biochem Biophys 294 1992 168 172
197. E.A. Shephard, I.R. Phillips, R.M. Bayney, S.F. Pike, and B.R. Rabin Quantification of NADPH: cytochrome P-450 reductase in liver microsomes by a specific radioimmunoassay technique Biochem J 211 1983 333 340
198. E.A. Shephard, I.R. Phillips, I. Santisteban, L.F. West, C.N. Palmer, and A. Ashworth Isolation of a human cytochrome P-450 reductase cDNA clone and localization of the corresponding gene to chromosome 7q11.2 Ann Hum Genet 53 1989 291 301
199. T. Shimada, R.L. Mernaugh, and F.P. Guengerich Interactions of mammalian cytochrome P450, NADPH-cytochrome P450 reductase, and cytochrome b(5) enzymes Arch Biochem Biophys 435 2005 207 216
200. T. Shimada, H. Yamazaki, M. Mimura, Y. Inui, and F.P. Guengerich Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians J Pharmacol Exp Ther 270 1994 414 423
201. T. Shimizu, T. Tateishi, M. Hatano, and Y. Fujii-Kuriyama Probing the role of lysines and arginines in the catalytic function of cytochrome P450d by site-directed mutagenesis. Interaction with NADPH-cytochrome P450 reductase J Biol Chem 266 1991 3372 3375
202. S.S. Shinde, M.P. Hay, A.V. Patterson, W.A. Denny, and R.F. Anderson Spin trapping of radicals other than the*OH radical upon reduction of the anticancer agent tirapazamine by cytochrome P450 reductase J Am Chem Soc 131 2009 14220 14221
203. S.C. Sim, W.L. Miller, X.B. Zhong, W. Arlt, T. Ogata, and X. Ding Nomenclature for alleles of the cytochrome P450 oxidoreductase gene Pharmacogenet Genomics 19 2009 565 566
204. S. Soneda, T. Yazawa, M. Fukami, M. Adachi, M. Mizota, and K. Fujieda Proximal promoter of the cytochrome P450 oxidoreductase gene: identification of microdeletions involving the untranslated exon 1 and critical function of the SP1 binding sites J Clin Endocrinol Metab 96 2011 E1881 E1887
205. H.W. Strobel, S.G. Nadler, and D.R. Nelson Cytochrome P-450: cytochrome P-450 reductase interactions Drug Metab Rev 20 1989 519 533
206. M. Subramanian, V. Agrawal, D. Sandee, H.K. Tam, W.L. Miller, and T.S. Tracy Effect of P450 oxidoreductase variants on the metabolism of model substrates mediated by CYP2C9.1, CYP2C9.2, and CYP2C9.3 Pharmacogenet Genomics 22 2012 590 597
207. K. Syed, C. Kattamuri, T.B. Thompson, and J.S. Yadav Cytochrome b(5) reductase-cytochrome b(5) as an active P450 redox enzyme system in Phanerochaete chrysosporium: atypical properties and in vivo evidence of electron transfer capability to CYP63A2 Arch Biochem Biophys 509 2011 26 32
208. M.K. Tee, N. Huang, I. Damm, and W.L. Miller Transcriptional regulation of the human P450 oxidoreductase gene: hormonal regulation and influence of promoter polymorphisms Mol Endocrinol 25 2011 715 731
209. R. Tenhunen, H.S. Marver, and R. Schmid The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase Proc Natl Acad Sci U S A 61 1968 748 755
210. R. Tenhunen, H.S. Marver, and R. Schmid Microsomal heme oxygenase. Characterization of the enzyme J Biol Chem 244 1969 6388 6394
211. D. Tomalik-Scharte, D. Maiter, J. Kirchheiner, H.E. Ivison, U. Fuhr, and W. Arlt Impaired hepatic drug and steroid metabolism in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency Eur J Endocrinol 163 2010 919 924
212. M. Tomkova, C.C. Marohnic, D. Gurwitz, O. Seda, B.S. Masters, and P. Martasek Identification of six novel P450 oxidoreductase missense variants in Ashkenazi and Moroccan Jewish populations Pharmacogenomics 13 2012 543 554
213. P. Urban, G. Truan, J.C. Gautier, and D. Pompon Xenobiotic metabolism in humanized yeast: engineered yeast cells producing human NADPH-cytochrome P-450 reductase, cytochrome b5, epoxide hydrolase and P-450s Biochem Soc Trans 21 1993 1028 1034
214. P. Utriainen, S. Laakso, J. Jaaskelainen, and R. Voutilainen Polymorphisms of POR, SULT2A1 and HSD11B1 in children with premature adrenarche Metabolism 61 2012 1215 1219
215. J.L. Vermilion, D.P. Ballou, V. Massey, and M.J. Coon Separate roles for FMN and FAD in catalysis by liver microsomal NADPH-cytochrome P-450 reductase J Biol Chem 256 1981 266 277
216. J.L. Vermilion, and M.J. Coon Highly purified detergent-solubilized NADPH-cytochrome P-450 reductase from phenobarbital-induced rat liver microsomes Biochem Biophys Res Commun 60 1974 1315 1322
217. B. Vincent, N. Morellet, F. Fatemi, L. Aigrain, G. Truan, and E. Guittet The closed and compact domain organization of the 70-kDa human cytochrome P450 reductase in its oxidized state as revealed by NMR J Mol Biol 420 2012 296 309
218. M.W. Voice, Y. Zhang, C.R. Wolf, B. Burchell, and T. Friedberg Effects of human cytochrome b5 on CYP3A4 activity and stability in vivo Arch Biochem Biophys 366 1999 116 124
219. J. Wang, and P.R. de Montellano The binding sites on human heme oxygenase-1 for cytochrome p450 reductase and biliverdin reductase J Biol Chem 278 2003 20069 20076
220. M. Wang, D.L. Roberts, R. Paschke, T.M. Shea, B.S. Masters, and J.J. Kim Three-dimensional structure of NADPH-cytochrome P450 reductase: prototype for FMN- and FAD-containing enzymes Proc Natl Acad Sci U S A 94 1997 8411 8416
221. S.L. Wang, J.F. Han, X.Y. He, X.R. Wang, and J.Y. Hong Genetic variation of human cytochrome p450 reductase as a potential biomarker for mitomycin C-induced cytotoxicity Drug Metab Dispos 35 2007 176 179
222. Y. Wang, J.P. Gray, V. Mishin, D.E. Heck, D.L. Laskin, and J.D. Laskin Distinct roles of cytochrome P450 reductase in mitomycin C redox cycling and cytotoxicity Mol Cancer Ther 9 2010 1852 1863
223. M.D. Waterfield, A. Del Favero, and C.H. Gray Effect of 1,4-dihydro-3,5-dicarbethoxycollidine on hepatic microsomal haem, cytochrome b5 and cytochrome P450 in rabbits and mice Biochim Biophys Acta 184 1969 470 473
224. C.H. Williams Jr., and H. Kamin Microsomal triphosphopyridine nucleotide-cytochrome c reductase of liver J Biol Chem 237 1962 587 595
225. L. Wu, J. Gu, H. Cui, Q.Y. Zhang, M. Behr, and C. Fang Transgenic mice with a hypomorphic NADPH-cytochrome P450 reductase gene: effects on development, reproduction, and microsomal cytochrome P450 J Pharmacol Exp Ther 312 2005 35 43
226. C. Xia, D. Hamdane, A.L. Shen, V. Choi, C.B. Kasper, and N.M. Pearl Conformational changes of NADPH-cytochrome P450 oxidoreductase are essential for catalysis and cofactor binding J Biol Chem 286 2011 16246 16260
227. C. Xia, S.P. Panda, C.C. Marohnic, P. Martasek, B.S. Masters, and J.J. Kim Structural basis for human NADPH-cytochrome P450 oxidoreductase deficiency Proc Natl Acad Sci U S A 108 2011 13486 13491
228. S. Yamano, T. Aoyama, O.W. McBride, J.P. Hardwick, H.V. Gelboin, and F.J. Gonzalez Human NADPH-P450 oxidoreductase: complementary DNA cloning, sequence and vaccinia virus-mediated expression and localization of the CYPOR gene to chromosome 7 Mol Pharmacol 36 1989 83 88
229. S. Yamaori, H. Yamazaki, A. Suzuki, A. Yamada, H. Tani, and T. Kamidate Effects of cytochrome b(5) on drug oxidation activities of human cytochrome P450 (CYP) 3As: similarity of CYP3A5 with CYP3A4 but not CYP3A7 Biochem Pharmacol 66 2003 2333 2340
230. K. Yanagibashi, and P.F. Hall Role of electron transport in the regulation of the lyase activity of C21 side-chain cleavage P-450 from porcine adrenal and testicular microsomes J Biol Chem 261 1986 8429 8433
231. G. Yang, Z. Fu, X. Chen, H. Yuan, H. Yang, and Y. Huang Effects of the CYP oxidoreductase Ala503Val polymorphism on CYP3A activity in vivo: a randomized, open-label, crossover study in healthy Chinese men Clin Ther 33 2011 2060 2070
232. Y. Yasukochi, and B.S. Masters Some properties of a detergent-solubilized NADPH-cytochrome c (cytochrome P-450) reductase purified by biospecific affinity chromatography J Biol Chem 251 1976 5337 5344
233. T. Yoshida, and G. Kikuchi Purification and properties of heme oxygenase from rat liver microsomes J Biol Chem 254 1979 4487 4491
234. J.J. Zhang, H. Zhang, X.L. Ding, S. Ma, and L.Y. Miao Effect of the P450 oxidoreductase*28 polymorphism on the pharmacokinetics of tacrolimus in Chinese healthy male volunteers Eur J Clin Pharmacol 2012 10.1007/s00228-012- 1432-1
235. L.H. Zhang, H. Rodriguez, S. Ohno, and W.L. Miller Serine phosphorylation of human P450c17 increases 17,20-lyase activity: implications for adrenarche and the polycystic ovary syndrome Proc Natl Acad Sci U S A 92 1995 10619 10623
236. X. Zhang, L. Li, X. Ding, and L.S. Kaminsky Identification of cytochrome P450 oxidoreductase gene variants that are significantly associated with the interindividual variations in warfarin maintenance dose Drug Metab Dispos 39 2011 1433 1439
237. S. Zhou, S. Yung Chan, B. Cher Goh, E. Chan, W. Duan, and M. Huang Mechanism-based inhibition of cytochrome P450 3A4 by therapeutic drugs Clin Pharmacokinet 44 2005 279 304