Protein and Gene Structure and Regulation of NADPH-Cytochrome P450 Oxidoreductase

  • A. L. Shen
  • C. B. Kasper
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 105)


The enzyme NADPH-cytochrome P450 oxidoreductase (NADPH: ferrihemoprotein oxidoreductase, E.C., hereafter referred to as reductase) is a component of the microsomal mixed function oxidase system, functioning in the endoplasmic reticulum (Williams and Kamin 1962; Phillips and Langdon 1962) and nuclear membrane (Kasper 1971) to catalyze electron transfer from NADPH to cytochrome P450 (Lu and Coon 1968). This 78-kDa flavin mononucleotide (FMN)- and flavin adenine dinucleotide (FAD)-containing (Iyanagi and Mason 1973) flavoprotein can also reduce other microsomal proteins, such as cytochrome b 5 (Enoch and Strittmatter 1979), heme oxygenase (Schacter et al. 1972), and fatty acid elongase (Ilan et al. 1981), as well as nonphysiologic electron acceptors such as cytochrome c, ferricyanide, menadione, and dichlorophenolindophenol (Williams and Kamin 1962). Reductase-catalyzed redox cycling of antitumor anthracycline compounds is a factor in the antitumor activity and toxicity of these compounds (Bachur et al. 1978, 1979), while electron transfer to mitomycin C produces the active form of this antitumor compound (Keyes et al. 1984). in conjunction with EDTA-Fe2+, cytochrome P450 or O2 , the reductase can initiate microsomal lipid peroxidation (Pederson et al. 1973; reviewed by Sevanian et al. 1990).


Flavin Adenine Dinucleotide Flavin Adenine Dinucleotide Reduce Nicotinamide Adenine Dinucleotide Reductase mRNA Isoalloxazine Ring 
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  1. Bachur NR, Gordon SL, Gee MV (1978) A general mechanism for microsomal activation of quinone anticancer agents to free radicals. Cancer Res 38: 1745–1750PubMedGoogle Scholar
  2. Bachur NR, Gordon SL, Gee MV, Kon H (1979) NADPH cytochrome P-450 reductase activation of quinone anticancer agents to free radicals. Proc Natl Acad Sci USA 76: 954–957PubMedCrossRefGoogle Scholar
  3. Balakrishnan G, Ramachandran M, Banerjee BD, Hussain QZ (1985) Effect of dietary protein, dichlorodiphenyltrichloroethane (DDT) and hexachlorocyclohexane ( HCH) on hepatic microsomal enzyme activity in rats. Br J Nutr 54: 563–566Google Scholar
  4. Barry M, Duenas-Laita A, Mathuna PM, Feely J (1987) Increase in renal cytochrome P-450 and NADPH cytochrome c reductase activity following drug inhibition of hepatic monooxygenase activity. Biochem Pharmacol 36: 768–769PubMedCrossRefGoogle Scholar
  5. Bastiaens PIH, Bonants PJM, Muller F, Visser AJWG (1989) Time-resolved fluorescence spectroscopy of NADPH-cytochrome P-450 reductase: demonstration of energy transfer between the two prosthetic groups. Biochemistry 28: 8416–8425PubMedCrossRefGoogle Scholar
  6. Benveniste I, Lesot A, Hasenfratz M-P, Durst F (1989) Immunochemical characterization of NADPH-cytochrome P-450 reductase from Jerusalem artichoke and other higher plants. Biochem J 259: 847–853PubMedGoogle Scholar
  7. Bernhardt R, Makower A, Janig G, Ruckpaul K (1984) Selective chemical modification of a functionally linked lysine in cytochrome P-450 LM2. Biochim Biophys Acta 785: 186–190PubMedCrossRefGoogle Scholar
  8. Bernhardt R, Kraft R, Otto A, Ruckpaul K (1988) Electrostatic interactions between cytochrome P-450 LM2 and NADPH-cytochrome P-450 reductase. Biomed Biochim Acta 7: 581–592Google Scholar
  9. Bhattacharyya AK, Lipka JJ, Waskell L, Tollin G (1991) Laser flash photolysis studies of the reduction kinetics of NADPH: cytochrome P-450 reductase. Biochemistry 30: 759–765PubMedCrossRefGoogle Scholar
  10. Black SD, Coon MJ (1982) Structural features of liver microsomal NADPH-cytochrome P-450 reductase. J Biol Chem 257: 5929–5938PubMedGoogle Scholar
  11. Black SD, French JS, Williams CH Jr, Coon MJ (1979) Role of a hydrophobic polypeptide in the N-terminal region of NADPH-cytochrome P-450 reductase in complex formation with P-450LM. Biochem Biophys Res Comm 91: 1528–1535PubMedCrossRefGoogle Scholar
  12. Bonants PJM, Muller F, Vervoort J, Edmondson DE (1990) A 31P-nuclear-magnetic-resonance study of NADPH-cytochrome P-450 reductase and of the Azotobacter flavodoxin/ferredoxin-NADP+ reductase complex. Eur J Biochem 190: 531–537PubMedCrossRefGoogle Scholar
  13. Bredt DS, Hwang PM, Glatt CE, Lowenstein C, Reed RR, Snyder SH (1991) Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase. Nature 351: 714–718PubMedCrossRefGoogle Scholar
  14. Brownie AC, Bhasker CR, Waterman MR (1988) Levels of adrenodoxin, NADPH- cytochrome P-450 reductase and cytochromes P-45011(3, P-450c21, P-450scc, in adrenal zona fasciculata-reticularis tissue from androgen-treated rats. Mol Cell Endocrinol 55: 15–20PubMedCrossRefGoogle Scholar
  15. Burnett RM, Darling GD, Kendall DS, LeQuesne ME, Mayhew SG, Smith WW, Ludwig ML (1974) The structure of the oxidized form of clostridial flavodoxin at 1.9-A resolution. Description of the flavin mononucleotide binding site. J Biol Chem 249: 4383–4392Google Scholar
  16. Chan RL, Carrillo N, Vallejos RH (1985) Isolation and sequencing of an active-site peptide from spinach ferredoxin-NADP+ oxidoreductase after affinity labeling with periodate-oxidized NADP+. Arch Biochem Biophys 240: 172–177PubMedCrossRefGoogle Scholar
  17. Cresteil T, Flinois JP, Pfister A, Leroux JP (1979) Effect of microsomal preparations and induction on cytochrome P-450-dependent monooxygenase in fetal and neonatal rat liver. Biochem Pharmacol 28: 2057–2063PubMedCrossRefGoogle Scholar
  18. Dailey HA, Strittmatter P (1979) Modification and identification of cytochrome b5 carboxyl groups involved in protein-protein interactions with cytochrome b5 reductase. J Biol Chem 254: 5388–5396PubMedGoogle Scholar
  19. Dee A, Carlson G, Smith C, Masters B, Waterman MR (1985) Regulation of synthesis and activity of bovine adrenocortical HADPH-cytochrome P-450 reductase by ACTH. Biochem Biophys Res Commun 128: 650–656PubMedCrossRefGoogle Scholar
  20. Drummond MH (1986) Structure predictions and surface charge of nitrogenase flavodoxins from Klebsiella pneumoniae and Azotobacter vinelandii. Eur J Biochem 159: 549–553PubMedCrossRefGoogle Scholar
  21. Dubourdieu M, Fox JL (1977) Amino acid sequence of Desulfovibrio vulgaris flavodoxin. J Biol Chem 252: 1453–1463PubMedGoogle Scholar
  22. Durham CR, Zhu H, Masters BS, Simpson ER, Mendelson CR (1985) Regulation of aromatase activity of rat granulosa cells: induction of synthesis of NADPH- cytochrome P-450 reductase by FSH and dibutyryl cyclic AMP. Mol Cell Endocrinol 40: 211–219PubMedCrossRefGoogle Scholar
  23. Enoch HG, Strittmatter P (1979) Cytochrome b5 reduction by NADPH-cytochrome P-450 reductase. J Biol Chem 254: 8976–8981PubMedGoogle Scholar
  24. Ghersi-Egea JF, Minn A, Daval JL, Jayyosi Z, Arnould V, Souhaili-El Amri H, Siest G (1989) NADPH: cytochrome P-450(c) reductase: biochemical characterization in rat brain and cultured neurons and evolution of activity during development. Neurochem Res 14: 883–888PubMedCrossRefGoogle Scholar
  25. Gonzalez FJ, Kasper CB (1982) Differential inducibility of nuclear envelope epoxide hydratase by trans-stilbene oxide and phénobarbital. Mol Pharmacol 21: 511–516PubMedGoogle Scholar
  26. Gonzalez FJ, Samore M, McQuiddy P, Kasper CB (1982) Effects of 2- acetylaminofluorene and N-hydroxy-2-acetylaminofluorene on the cellular levels of epoxide hydratase, cytochrome P-450b, and NADPH-cytochrome c (P-450) oxidoreductase messenger ribonucleic acids. J Biol Chem 257: 11032–11036PubMedGoogle Scholar
  27. Gum JR, Strobel HW (1981) Isolation of the membrane-binding peptide of NADPH-cytochrome P-450 reductase. J Biol Chem 256: 7478–7486PubMedGoogle Scholar
  28. Haglund L, Kohler C, Haaparanta T, Goldstein M, Gustafsson JA (1984) Presence of NADPH-cytochrome P450 reductase in central catecholaminergic neurones. Nature 307: 259–262PubMedCrossRefGoogle Scholar
  29. Haniu M, Iyanagi T, Legesse K, Shively JE (1984) 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: 13703–13711PubMedGoogle Scholar
  30. Haniu M, Iyanagi T, Miller P, Lee TD, Shively JE (1986) Complete amino acid sequence of NADPH-cytochrome P-450 reductase from porcine hepatic microsomes. Biochemistry 25: 7906–7911PubMedCrossRefGoogle Scholar
  31. Haniu M, McManus ME, Birkett DJ, Lee TD, Shively JE (1989) Structural and functional analysis of NADPH-cytochrome P-450 reductase from human liver: complete sequence of human enzyme and NADPH-binding sites. Biochemistry 28: 8639–8645PubMedCrossRefGoogle Scholar
  32. Hanukoglu I, Gutfinger T (1989) cDNA sequence of adrenodoxin reductase - identification of NADP-binding sites in oxidoreductases. Eur J Biochem 180: 479–484Google Scholar
  33. Hardwick JP, Gonzalez FJ, Kasper CB (1983) Transcriptional regulation of rat liver epoxide hydratase, NADPH-cytochrome P-450 oxidoreductase, and cytochrome P-450b genes by phénobarbital. J Biol Chem 258: 8081–8085PubMedGoogle Scholar
  34. Hetu C, Joly JG (1988) Effect of chronic acetone administration on ethanol- inducible monooxygenase activities in the rat. Biochem Pharmacol 37: 421–426PubMedCrossRefGoogle Scholar
  35. Ilan Z, Ilan R, Cinti DL (1981) Evidence for a new physiological role of hepatic NADPH: ferricytochrome (P450) oxidoreductase. J Biol Chem 256: 10066–10072PubMedGoogle Scholar
  36. Inano H, Tamaoki B (1986) Chemical modification of NADPH-cytochrome P-450 reductase. Eur J Biochem 155: 485–489PubMedCrossRefGoogle Scholar
  37. Iyanagi T, Mason HS (1973) Some properties of hepatic reduced nicotinamide adenine dinucleotide phosphate-cytochrome c reductase. Biochemistry 12: 2297–2308PubMedCrossRefGoogle Scholar
  38. Iyanagi T, Makino N, Mason HS (1974) Redox properties of the reduced nicotinamide adenine dinucleotide phosphate-cytochrome P-450 and reduced nicotinamide adenine dinucleotide-cytochrome b5 reductases. Biochemistry 13: 1701PubMedCrossRefGoogle Scholar
  39. Iyanagi T, Makino R, Anan FK (1981) Studies on the microsomal mixed-function oxidase system: mechanism of action of hepatic NADPH-cytochrome P-450 reductase. Biochemistry 20: 1722–1730PubMedCrossRefGoogle Scholar
  40. Joly J-G, Ishii H, Teschke R, Hasumara Y, Lieber CS (1973) Effect of chronic ethanol feeding on the activities and submicrosomal distribution of reduced nicotinamide adenine dinucleotide phosphate-cytochrome P-450 reductase and the demethylases for aminopyrine and ethylmorphine. Biochem Pharmacol 22: 1532–1535PubMedCrossRefGoogle Scholar
  41. Karplus PA, Walsh KA, Herriott JR (1984) Amino acid sequence of spinach ferredoxin: NADP+ oxidoreductase. Biochemistry 23: 6576–6583Google Scholar
  42. Karplus PA, Daniels MJ, Herriott JR (1991) Atomic structure of ferredoxin-NADP+ reductase: prototype for a structurally novel flavoenzyme family. Science 251: 60–66PubMedCrossRefGoogle Scholar
  43. Kasper CB (1971) Biochemical distinctions between the nuclear and microsomal membranes from rat hepatocytes: the effect of phenobarbital administration. J Biol Chem 246: 577–581PubMedGoogle Scholar
  44. Katagiri M, Murakami H, Yabusaki Y, Sugiyama T (1986) Molecular cloning and sequence analysis of full-length cDNA for rabbit liver NADPH-cytochrome P-450 reductase mRNA. J Biochem (Tokyo) 100: 945–954Google Scholar
  45. Keyes SR, Fracasso PM, Heimbrook DC, Rockwell S, Sligar SG, Sartorelli AC (1984) Role of NADPH: cytochrome c reductase and DT diaphorase in the biotransformation of mitomycin C. Cancer Res 44: 5638–5643PubMedGoogle Scholar
  46. Kitigawa H, Fijita S, Suzuki T, Kitani K (1985) Disappearance of sex differences in rat liver drug metabolism with age. Biochem Pharmacol 34: 579–581CrossRefGoogle Scholar
  47. Kurzban GP, Strobel HW (1986) Preparation and characterization of FAD-dependent NADPH-cytochrome P-450 reductase. J Biol Chem 261: 7824–7830PubMedGoogle Scholar
  48. Lazar T, Ehrig H, Lumper L (1977) The functional role of thiol groups in protease-solubilized NADPH-cytochrome c reductase from pork-liver microsomes. Eur J Biochem 76: 365–371PubMedCrossRefGoogle Scholar
  49. Lu AYH, Coon MJ (1968) Role of hemoprotein P-450 in fatty acid ω-hydroxylation in a soluble enzyme system from liver microsomes. J Biol Chem 243: 1331–1332PubMedGoogle Scholar
  50. Lumper L, Busch F, Dzelic S, Henning J, Lazar T (1980) Studies on the cosubstrate site of protease solubilized NADPH-cytochrome P450 reductase. Int J Pept Protein Res 16: 83–96PubMedCrossRefGoogle Scholar
  51. Lundgren B, DePierre JW (1987) Induction of xenobiotic-metabolizing enzymes and peroxisome proliferation in rat liver caused by dietary exposure to di(2- ethylhexyl)phosphate. Xenobiotica 17: 585–593PubMedCrossRefGoogle Scholar
  52. Masters BBS, Kamin H, Gibson QH, Williams CH (1965) Studies on the mechanism of microsomal triphosphopyridine nucleotide-cytochrome c reductase. J Biol Chem 240: 921–931PubMedGoogle Scholar
  53. Masters BSS, Otvos JD, Kasper CB, Shen A, Rajagopalan J, Narayanasami R, Okita JR, McCabe TJ (1990) 31P NMR studies on purified, native and cloned, expressed forms of NADPH-cytochrome P-450 reductase. Fed Proc 4: A2323Google Scholar
  54. Müller K, Linder D, Lumper L (1990) The cosubstrate NADP(H) protects lysine 601 in the porcine NADPH-cytochrome P-450 reductase against pyridoxylation. FEBS Lett 260: 289–290PubMedCrossRefGoogle Scholar
  55. Nadler SG, Strobel HW (1988) Role of electrostatic interactions in the reaction of NADPH-cytochrome P-450 reductase with cytochromes P-450. Arch Biochem Biophys 261: 418–429PubMedCrossRefGoogle Scholar
  56. Narayanasami R, Otvos JD, Horowitz P, Kasper CB, Shen AL, Okita JR, Camitta M, Masters BSS (1991) Structure-function studies on purified, native and cloned, expressed forms of NADPH-cytochrome P-450 reductase utilizing 31P NMR and fluorescence spectroscopy. Fed Proc 5: A472Google Scholar
  57. Ng S, Smith MB, Smith HT, Millett F (1977) Effect of modification of individual cytochrome c lysines on the reaction with cytochrome b5. Biochemistry 16: 4975–4978PubMedCrossRefGoogle Scholar
  58. Nisimoto Y (1986) Localization of cytochrome c-binding domain on NADPH-cytochrome P-450 reductase. J Biol Chem 261: 14232–14239PubMedGoogle Scholar
  59. Nisimoto Y, Shilbata Y (1982) Studies on FAD- and FMN-binding domains in NADPH-cytochrome P-450 reductase from rabbit liver microsomes. J Biol Chem 257: 12532–12539PubMedGoogle Scholar
  60. Nisimoto Y, Hayashi F, Akutsu H, Kyogoku Y, Shibata Y (1984) Photochemically induced dynamic nuclear polarization study on microsomal NADPH-cytochrome P-450 reductase. J Biol Chem 259: 2480–2483PubMedGoogle Scholar
  61. Nisimoto Y, Otsuka-Murakami H (1988) Cytochrome b 5, cytochrome c and cytochrome P-450 interactions with NADPH-cytochrome P-450 reductase in phospholipid vesicles. Biochemistry 27: 5869–5876PubMedCrossRefGoogle Scholar
  62. Ostrowski J, Barber MJ, Rueger DC, Miller BE, Siegel LM, Kredich NM (1989) Characterization of the flavoprotein moieties of NADPH-sulfite reductase from Salmonella typhimurium and Escherichia coli. Physicochemical and catalytic properties, amino acid sequence deduced from DNA sequence of cysJ, and comparison with NADPH-cytochrome P-450 reductase. J Biol Chem 264: 15796–15808PubMedGoogle Scholar
  63. Otvos JD, Krum DP, Masters BSS (1986) Localization of the free radical on the flavin mononucleotide of the air-stable semiquinone state of NADPH- cytochrome P-450 reductase using 3lP NMR spectroscopy. Biochemistry 25: 7220–7228PubMedCrossRefGoogle Scholar
  64. Pai EF, Schulz GE (1983) The catalytic mechanism of glutathione reductase as derived from X-ray diffraction analyses of reaction intermediates. J Biol Chem 258: 1752–1757PubMedGoogle Scholar
  65. Pederson TC, Buege JA, Aust SD (1973) Microsomal electron transport: the role of reduced nicotinamide adenine dinucleotide phosphate-cytochrome c reductase in liver microsomal lipid peroxidation. J Biol Chem 248: 7134–7141PubMedGoogle Scholar
  66. Phillips AH, Langdon RG (1962) Hepatic triphosphopyridine nucleotide-cytochrome c reductase: isolation, characterization, and kinetic studies. J Biol Chem 237: 2652–2660PubMedGoogle Scholar
  67. Piriou A, Jacqueson A, Warnet JM, Claude JR (1983) Enzyme induction with high doses of rifampicin in Wistar rats. Toxicol Lett 17: 301–306PubMedCrossRefGoogle Scholar
  68. Poland A, Glover E (1974) Comparison of 2,3,7,8-tetrachlorodibenzo-p-dioxin, a potent inducer of aryl hydrocarbon hydroxylase, with 3-methylcholanthrene. Mol Pharmacol 10: 349–359PubMedGoogle Scholar
  69. Porter TD (1991) An unusual yet strongly conserved flavoprotein reductase in bacteria and mammals. Trends Biochem Sci 16: 154–158PubMedCrossRefGoogle Scholar
  70. Porter TD, Beck TW, Kasper CB (1990) NADPH-cytochrome P-450 oxidoreductase gene organization correlates with structural domains of the protein. Biochemistry 29: 9814–9818PubMedCrossRefGoogle Scholar
  71. Porter TD, Kasper CB (1985) Coding nucleotide sequence of rat NADPH-cytochrome P-450 oxidoreductase cDNA and identification of flavin-binding domains. Proc Natl Acad Sci USA 82: 973–977PubMedCrossRefGoogle Scholar
  72. Porter TD, Kasper CB (1986) NADPH-cytochrome P-450 oxidoreductase: flavin mononucleotide and flavin adenine dinucleotide domains evolved from different flavoproteins. Biochemistry 25: 1682–1687PubMedCrossRefGoogle Scholar
  73. Prasad JS, Crankshaw DL, Erickson RR, Elliot CE (1985) Studies on the effect of chronic consumption of moderate amounts of ethanol on male rat hepatic microsomal drug-metabolizing activity. Biochem Pharmacol 34: 3427–3431PubMedCrossRefGoogle Scholar
  74. Reed CJ, Lock EA, De Matteis F (1986) NADPH: cytochrome P-450 reductase in olfactory epithelium. Relevance to cytochrome P-450-dependent reactions. Biochem J 240: 585–592PubMedGoogle Scholar
  75. Rice SA, Talcott RE (1979) Effects of isoniazid treatment on selected hepatic mixed-function oxidases. Drug Metab Dispos 7: 260–262PubMedGoogle Scholar
  76. Rossman MG, Liljas A, Branden C-I, Banaszak LJ (1975) Evolutionary and structural relationships among dehydrogenases. In: Boyer PD (ed) The enzymes, vol 11. Academic, New York, p 62Google Scholar
  77. Ruettinger RT, Wen L-P, Fulco AJ (1989) Coding nucleotide, 5′ regulatory, and deduced amino acid sequences of P-450BM-3, a single peptide cytochrome P-450: NADPH-P-450 reductase from Bacillus megaterium. J Biol Chem 264: 10987–10995PubMedGoogle Scholar
  78. Schacter BA, Nelson EB, Marver HS, Masters BSS (1972) Immunochemical evidence for an association of heme oxygenase with the microsomal electron transport system. J Biol Chem 247: 3601–3607PubMedGoogle Scholar
  79. Scrutton NS, Berry A, Perham RN (1990) Redesign of the coenzyme specificity of a dehydrogenase by protein engineering. Nature 343: 38–43PubMedCrossRefGoogle Scholar
  80. Sevanian A, Nordenbrand K, Kim E, Ernster L, Hochstein P (1990) Microsomal lipid peroxidation: the role of NADPH-cytochrome P450 reductase and cytochrome P450. Free Radic Biol Med 8: 145–152PubMedCrossRefGoogle Scholar
  81. Shen AL, Kasper CB (1990) Localization of the cytochrome c binding site of NADPH-cytochrome P-450 oxidoreductase. Fed Proc 4: A2322Google Scholar
  82. Shen AL, Porter TD, Wilson TE, Kasper CB (1989) Structural analysis of the FMN binding domain of NADPH-cytochrome P-450 oxidoreductase by site-directed mutagenesis. J Biol Chem 264: 7584–7589PubMedGoogle Scholar
  83. Shen AL, Christensen MJ, Kasper CB (1991) NADPH-cytochrome P-450 oxidoreductase: the role of cysteine 566 in catalysis and cofactor binding. J Biol Chem 266: 19976–19980PubMedGoogle Scholar
  84. Shen ES, Guengerich FP, Olson JR (1989) Biphasic response for hepatic microsomal enzyme induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin in C57BL/6J and DBA/2J mice. Biochem Pharmacol 38: 4075–4084PubMedCrossRefGoogle Scholar
  85. Shephard EA, Phillips IR, Pike SF, Ashworth A, Rabin BR (1982) Differential effect of phenobarbital and beta-naphthoflavone on the mRNAs coding for cytochrome P450 and NADPH cytochrome P450 reductase. FEBS Lett 150: 375–380PubMedCrossRefGoogle Scholar
  86. Shephard EA, Phillips IR, Santisteban E, West LF, Palmer CNA (1989) Isolation of a human cytochrome P-450 reductase cDNA clone and localization of the corresponding gene to chromosome 7qll.2. Ann Hum Genet 53: 291–301PubMedCrossRefGoogle Scholar
  87. Shimizu T, Tateishi T, Hatano M, Fujii-Kuriyama Y (1991) Probing the role of lysines and arginines in the catalytic function of cytochrome P450d by site-directed mutagenesis. J Biol Chem 266: 3372–3375PubMedGoogle Scholar
  88. Shiraki H, Guengerich FP (1984) Turnover of membrane proteins: kinetics of induction and degradation of seven forms of rat liver microsomal cytochrome P-450, NADPH-cytochrome P-450 reductase, and epoxide hydrolase. Arch Biochem Biophys 235: 86–96PubMedCrossRefGoogle Scholar
  89. Simmons DL, Kasper CB (1989) Quantitation of mRNAs specific for the mixed- function oxidase system in rat liver and extrahepatic tissues during development. Arch Biochem Biophys 271: 10–20PubMedCrossRefGoogle Scholar
  90. Simmons DL, Lalley PA, Kasper CB (1985) Chromosomal assignments of genes coding for components of the mixed function oxidase system in mice. Genetic localization of the cytochrome P-450PCN and P-450PB gene families and the NADPH-cytochrome P-450 oxidoreductase, and epoxide hydratase genes. J Biol Chem 260: 515–521PubMedGoogle Scholar
  91. Simmons DL, McQuiddy P, Kasper CB (1987) Induction of the hepatic mixed-function oxidase system by synthetic glucocorticoids: transcriptional and posttranscriptional regulation. J Biol Chem 262: 326–332PubMedGoogle Scholar
  92. Sugiyama T, Nisimoto Y, Mason HS, Loehr TM (1985) Flavins of NADPH-cytochrome P-450 reductase: evidence for structural alteration of flavins in their one-electron-reduced semiquinone state from resonance Raman spectroscopy. Biochemistry 24: 3012–3019PubMedCrossRefGoogle Scholar
  93. Sutter TR, Loper JC (1989) Disruption of the Saccharomyces cerevisiae gene for NADPH-cytochrome P450 reductase causes increased sensitivity to ketoconazole. Biochem Biophys Res Commun 160: 1257–1266PubMedCrossRefGoogle Scholar
  94. Sutter TR, Sangard D, Loper JC (1990) Isolation and characterization of the alkane- inducible NADPH-cytochrome P-450 oxidoreductase gene from Candida tropicalis. Identification of invariant residues within similar amino acid sequences of divergent flavoproteins. J Biol Chem 265: 16428–16436Google Scholar
  95. Takeshita M, Tamura M, Yubisui (1983) Microsomal electron-transport reductase activities and fatty acid elongation in rat brain. Biochem J 214: 751–756Google Scholar
  96. Tamburini P, Schenkman JB (1986) Differences in the mechanism of functional interaction between NADPH-cytochrome P-450 reductase and its redox partners. Mol Pharmacol 30: 178–185PubMedGoogle Scholar
  97. Tamburini PP, Schenkman JB (1987) Purification to homogeneity and enzymological characterization of a functional covalent complex composed of cytochromes P-450 isozyme 2 and b 5 from rabbit liver. Proc Natl Acad Sci USA 84: 11–15PubMedCrossRefGoogle Scholar
  98. Tamburini PP, Jansson I, Favreau LV, Backes WL, Schenkman JB (1986a) Differences in the spectral interactions between NADPH-cytochrome P-450 reductase and a series of cytochrome P-450 enzymes. Biochem Biophys Res Commun 137: 437–442PubMedCrossRefGoogle Scholar
  99. Tamburini PP, MacFarquhar S, Schenkman JB (1986b) Evidence of binary complex formations between cytochrome P-450, cytochrome b5, and NADPH- cytochrome P-450 reductase of hepatic microsomes. Biochem Biophys Res Commun 134: 519–526PubMedCrossRefGoogle Scholar
  100. Thomas PE, Reik LM, Ryan DE, Levin W (1981) Regulation of three forms of cytochrome P-450 and epoxide hydrolase in rat liver microsomes. J Biol Chem 256: 1044–1052PubMedGoogle Scholar
  101. Tu YY, Peng R, Chang Z-F, Yang CS (1983) Induction of a high affinity nitrosamine demethylase in rat liver microsomes by acetone and isopropanol. Chem Biol Interact 44: 247–255PubMedCrossRefGoogle Scholar
  102. Urenjak J, Linder D, Lumper (1987) Structural comparison between the trout and mammalian hydrophilic domain of NADPH-cytochrome P-450 reductase. J Chromatogr 397: 123–136Google Scholar
  103. van der Hoeven T, Galivan J (1987) The effect of dexamethasone, insulin, and triiodothyronine on microsomal NADPH-cytochrome-c (P-450) reductase in primary cultures of isolated hepatocytes. Biochim Biophys Acta 931: 59–67PubMedCrossRefGoogle Scholar
  104. Vermilion JL, Coon MJ (1978) Identification of the high and low potential flavins of liver microsomal NADPH-cytochrome P-450 reductase. J Biol Chem 253: 8812–8819PubMedGoogle Scholar
  105. Vermilion JL, Ballou DP, Massey V, Coon MJ (1981) Separate roles for FMN and FMN in catalysis by liver microsomal NADPH-cytochrome P-450 reductase. J Biol Chem 256: 266–277PubMedGoogle Scholar
  106. Vogel F, Lumper L (1986) Complete structure of the hydrophilic domain in the porcine NADPH-cytochrome P-450 reductase. Biochem J 236: 871–878PubMedGoogle Scholar
  107. von Heijne G (1985) Structural and thermodynamic aspects of the transfer of proteins into and across membranes. Curr Top Membr Trans 24: 151Google Scholar
  108. Watenpaugh KD, Sieker LC, Jensen LH (1973) The binding of riboflavin-5′-phosphate in a flavoprotein: flavodoxin at 2.0-A resolution. Proc Natl Acad Sci USA 70: 3857–3860PubMedCrossRefGoogle Scholar
  109. Waxman DJ, Morrissey JJ, Leblanc GA (1989) Hypophysectomy differentially alters P-450 protein levels and enzyme activities in rat liver: pituitary control of hepatic NADPH-cytochrome P-450 reductase. Mol Pharmacol 35: 519–525PubMedGoogle Scholar
  110. Wierenga RK, De Maeyer MCH, Hoi WGJ (1985) Interaction of pyrophosphate moieties with α-helixes in dinucleotide binding proteins. Biochemistry 24: 1346–1357CrossRefGoogle Scholar
  111. Williams CH, Kamin H (1962) Microsomal triphosphopyridine nucleotide-cytochrome c reductase of liver. J Biol Chem 237: 587–595PubMedGoogle Scholar
  112. Wolf CR, Moll E, Friedberg T, Oesch F, Buchmann A, Kuhlmann WD, Kunz HW (1984) Characterization, localization, and regulation of a novel phenobarbital-inducible form of cytochrome P450, compared with three further P450 isozymes, NADPH P450-reductase, glutathione transferase and microsomal epoxide hydrolase. Carcinogenesis 5: 993–1001PubMedCrossRefGoogle Scholar
  113. Wu H-Q, Masset-Brown J, Tweedie DJ, Milewich L, Frenkel RA, Martin-Wixtrom C, Estabrook R, Prough R (1989) Induction of microsomal NADPH- cytochrome P-450 reductase and cytochrome P-450IVAl(P-450Laco) by dehydroepiandrosterone in rats: a possible peroxisomal proliferator. Cancer Res 49: 2337–2343PubMedGoogle Scholar
  114. Yabusaki Y, Murakami H, Ohkawa H (1988) Primary structure of Saccharomyces cerevisiae NADPH-cytochrome P-450 reductase deduced from nucleotide sequence of its cloned gene. J Biochem (Tokyo) 103: 1004–1010Google Scholar

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© Springer-Verlag Berlin Heidelberg 1993

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  • A. L. Shen
  • C. B. Kasper

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