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Recent advances in P450 research

Abstract

P450 enzymes comprise a superfamily of heme-containing proteins that catalyze oxidative metabolism of structurally diverse chemicals. Over the past few years, there has been significant progress in P450 research on many fronts and the information gained is currently being applied to both drug development and clinical practice. Recently, a major accomplishment occurred when the structure of a mammalian P450 was determined by crystallography. Results from these studies will have a major impact on understanding structure-activity relationships of P450 enzymes and promote prediction of drug interactions. In addition, new technologies have facilitated the identification of several new P450 alleles. This information will profoundly affect our understanding of the causes attributed to interindividual variations in drug responses and link these differences to efficacy or toxicity of many therapeutic agents. Finally, the recent accomplishments towards constructing P450 null animals have afforded determination of the role of these enzymes in toxicity. Moreover, advances have been made towards the construction of humanized transgenic animals and plants. Overall, the outcome of recent developments in the P450 arena will be safer and more efficient drug therapies.

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References

  1. Omura T . Forty years of cytochrome P450 Biochem Biophys Res Commun 1999 266: 690–698

    Article  CAS  Google Scholar 

  2. Stegeman JJ, Livingstone DR . Forms and functions of cytochrome P450 Comp Biochem Physiol [C] 1998 121: 1–3

    CAS  Google Scholar 

  3. Nelson DR . Cytochrome P450 and the individuality of species Arch Biochem Biophys 1999 369: 1–10

    Article  CAS  Google Scholar 

  4. Ingelman-Sundberg M, Oscarson M, McLellan RA . Polymorphic human cytochrome P450 enzymes: an opportunity for individualized drug treatment Trends Pharmacol Sci 1999 20: 342–349

    Article  CAS  Google Scholar 

  5. Podust L, Poulos T, Waterman M . Crystal structure of cytochrome P450 14α-sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors Proc Natl Acad Sci USA 2001 98: 3068–3073

    Article  CAS  Google Scholar 

  6. Peterson JA, Graham SE . A close family resemblance: the importance of structure in understanding cytochromes P450 Structure 1998 6: 1079–1085

    Article  CAS  Google Scholar 

  7. Graham SE, Peterson JA . How similar are P450s and what can their differences teach us? Arch Biochem Biophys 1999 369: 24–29

    Article  CAS  Google Scholar 

  8. Gotoh O . Substrate recognition sites in cytochrome P450 family 2 (CYP2) proteins inferred from comparative analyses of amino acid and coding nucleotide sequences J Biol Chem 1992 267: 83–90

    CAS  Google Scholar 

  9. Williams PA, Cosme J, Sridhar V, Johnson EF, McRee DE . Mammalian microsomal cytochrome P450 monooxygenase: structural adaptations for membrane binding and functional diversity Mol Cell 2000 5: 121–131

    Article  CAS  Google Scholar 

  10. Cosme J, Johnson EF . Engineering microsomal cytochrome P4502C5 to be a soluble, monomeric enzyme—mutations that alter aggregation, phospholipid dependence of catalysis, and membrane binding J Biol Chem 2000 275: 2545–2553

    Article  CAS  Google Scholar 

  11. Watkins RE, Wisely GB, Moore LB, Collins JL, Lambert MH, Williams SP et al. The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity Science 2001 292: 2329–2333

    Article  CAS  Google Scholar 

  12. Evans WE, Relling MV . Pharmacogenomics: translating functional genomics into rational therapeutics Genome 1999 286: 487–491

    CAS  Google Scholar 

  13. Nebert DW . Suggestions for the nomenclature of human alleles: relevance to ecogenetics, pharmacogenetics and molecular epidemiology Pharmacogenetics 2000 10: 279–290

    Article  CAS  Google Scholar 

  14. Dover G . Molecular drive in multigene families: how biological novelties arise, spread and are assimilated Trends Genet 1986 2: 159–165

    Article  CAS  Google Scholar 

  15. Hodgson J, Marshall A . Pharmacogenomics: will the regulators approve? Nat Biotechnol 1998 16: 13–15

    Article  Google Scholar 

  16. Marshall A . Getting the right drug into the right patient Nat Biotechnol 1998 16: 9–12

    Article  Google Scholar 

  17. Howell WM, Jobs M, Gyllensten U, Brookes AJ . Dynamic allele-specific hybridization: a new method for scoring single nucleotide polymorphisms Nat Biotechnol 1999 17: 88

    Article  Google Scholar 

  18. Bruning T, Able J, Koch B, Lorenzen K, Harth V, Donat S et al. Real-time PCR-analysis of the cytocrhome P450 1B1 codon 432-polymorphims Arch Toxicol 1999 73: 427–436

    Article  CAS  Google Scholar 

  19. Scarlett LA, Madani S, Shen DD, Ho RJY . Development and characterization of a rapid and comprehensive genotyping assay to detect the most common variants in cytochrome P450 2D6 Pharm Res 2000 17: 242–246

    Article  CAS  Google Scholar 

  20. Sohda T . Allele-specific polymerase chain reaction for genotyping human cytochrome P450 2E1 J Clin Lab Anal 1999 13: 205–208

    Article  CAS  Google Scholar 

  21. Shimada T, Tsumura F, Yamazaki H, Guengerich FP, Inoue K . Characterization of (±)-bufuraolol hydroxylation activities in liver microsomes of Japanese and Caucasian subjects genotyped for CYP2D6 Pharmacogenetics 2001 11: 143–156

    Article  CAS  Google Scholar 

  22. Wedlund PJ . The CYP2C19 enzyme polymorphism Pharmacology 2000 61: 174–183

    Article  CAS  Google Scholar 

  23. de Morais SM, Wilkinson GR, Blaisdell J, Meyer UA, Nakamura K, Goldstein JA . Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese Mol Pharmacol 1994 46: 594–598

    CAS  PubMed  Google Scholar 

  24. Ibeanu GC, Blaisdell J, Ferguson RJ, Ghanayem BI, Brosen K, Benhamou S et al. A novel transversion in the intron 5 donor splice junction of CYP2C19 and a sequence polymorphism in exon 3 contribute to the poor metabolizer phenotype for the anticonvulsant drug S-mephenytoin J Pharmacol Exp Ther 1999 290: 635–640

    CAS  PubMed  Google Scholar 

  25. Ferguson RJ, de Morais SMF, Benhamou S, Bouchardy C, Blaisdell J, Ibeanu G et al. A new genetic defect in human CYP2C19. Mutation of the initiation codon is responsible for poor metabolism of S-mephenytoin J Pharmacol Exp Ther 1998 284: 356–361

    CAS  PubMed  Google Scholar 

  26. Ibeanu GC, Blaisdell J, Ghanayem BI, Beyeler C, Benhamou S, Bouchardy C et al. An additional defective allele, CYP2C19*5, contributes to the S-mephenytoin poor metabolizer phenotype in Caucasians Pharmacogenetics 1998 8: 129–135

    Article  CAS  Google Scholar 

  27. Ibeanu GC, Goldstein JA, Meyer U, Benhamou S, Bouchardy C, Dayer P et al. Identification of new human CYP2C19 alleles (CYP2C19*6 and CYP2C19*2B) in a Caucasian poor metabolizer of mephenytoin J Pharmacol Exp Ther 1998 286: 1490–1495

    CAS  PubMed  Google Scholar 

  28. Nunoya K, Yokoi T, Takahashi Y, Kimura K, Kinoshita M, Kamataki T . Homologous unequal cross-over within the human CYP2A gene cluster as a mechanism for the deletion of the entire CYP2A6 gene associated with the poor metabolizer phenotype J Biochem (Tokyo) 1999 126: 402–407

    Article  CAS  Google Scholar 

  29. Ariyoshi N, Sawamura Y, Kamataki T . A novel single nucleotide polymorphism altering stability and activity of CYP2A6 Biochem Biophys Res Commun 2001 281: 810–814

    Article  CAS  Google Scholar 

  30. Kuehl P, Zhang J, Lin Y, Lamba J, Mahfoud A, Schuetz J et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression Nature Genet 2001 27: 383–391

    Article  CAS  Google Scholar 

  31. Sullivan-Klose TH, Ghanayem BI, Bell DA, Zhang ZY, Kaminsky LS, Shenfield GM et al. The role of the CYP2C9-Leu359 allelic variant in the tolbutamide polymorphism Pharmacogenetics 1996 6: 341–349

    Article  CAS  Google Scholar 

  32. Kitagawa K, Kunugita N, Kitagawa M, Kawamoto T . CYP2A6*6, a novel polymorphism in cytochrome P4502A6, has a single amino acid substitution (R128Q) that inactivates enzymatic activity J Biol Chem 2001 276: 17830–17835

    Article  CAS  Google Scholar 

  33. Pitarque M, Von Richter O, Oke B, Berkkan H, Oscarson M, Ingelman-Sunberg M . Identification of a single nucleotide polymorphism in the TATA box of the CYP2A6 gene: impairment of its promoter activity Biochem Biophys Res Commun 2001 284: 455–460

    Article  CAS  Google Scholar 

  34. Dai D, Blaisdell J, Ghahayem B, Anders E-M . Genetic polymorphism of human CYP2C8 and their effects on metabolism of anticancer drug paclitaxel FASEB J 2000 14: A1338

    Google Scholar 

  35. Ariyosh N, Miyazaki M, Toide K, Swamura Y, Kamataki T . A single nucleotide polymorphism of CYP2B6 found in Japanese enhances catalytic activity by autoactivation Biochem Biophys Res Commun 2001 281: 1256–1260

    Article  Google Scholar 

  36. Gonzalez FJ . The study of xenobiotic-metabolizing enzymes and their role in toxicity in vivo using targeted gene disruption Toxicol Lett 1998 103: 161–166

    Article  Google Scholar 

  37. Buters JTM, Doehmer J, Gonzalez FJ . Cytochrome P450-null mice Drug Metab Rev 1999 31: 437–447

    Article  CAS  Google Scholar 

  38. Westphal H . Transgenic mammals and biotechnology FASEB J 1989 3: 117–120

    Article  CAS  Google Scholar 

  39. McKinnon RA, Nebert DW . Cytochrome P450 knockout mice: new toxicological models Clin Exp Pharmacol Physiol 1998 25: 783–787

    Article  CAS  Google Scholar 

  40. Ghanayem BI, Wang H, Sumner S . Using cytochrome P450 gene knock-out mice to study chemical metabolism, toxicity, and carcinogenicity Toxicol Pathol 2000 28: 839–850

    Article  CAS  Google Scholar 

  41. Pineau T, Fernandez-Salguero P, Lee SST, McPhail T, Ward JM, Gonzalez FJ . Neonatal lethality associated with respiratory distress in mice lacking cytochrome P450 1A2 Proc Natl Acad Sci USA 1995 92: 5134–5138

    Article  CAS  Google Scholar 

  42. Dalton TP, Dieter MZ, Matlib RS, Childs NL, Shertzer HG, Genter MB et al. Targeted knockout of cyp1a1 gene does not alter hepatic constitutive expression of other genes in the mouse [Ah] battery Biochem Biophys Res Commun 2000 267: 184–189

    Article  CAS  Google Scholar 

  43. Schmidt JV, Su GH-T, Reddy JK, Simon M, Bradfield CA . Characterization of a murine Ahr null allele: involvement of the Ah receptor in hepatic growth and development Proc Natl Acad Sci USA 1996 93: 6731–6736

    Article  CAS  Google Scholar 

  44. Liang HCL, Li H, McKinnon RA, Duffy JJ, Potter SS, Puga et al. Cyp1a2(−/−) null mutant mice develop normally but show deficient drug metabolism Proc Natl Acad Sci USA 1996 93: 1671–1676

    Article  CAS  Google Scholar 

  45. Heidel SM, MacWilliams PS, Baird WM, Dashwood M, Buters JTM, Gonzalez FJ et al. Cytrochrome P4501B1 mediates induction of bone marrow cytoxocity and preleukemia cells in mice treated with 7,12-dmethylbenz[a]anthracene Cancer Res 2000 60: 3454–3460

    CAS  Google Scholar 

  46. Buters JTM, Sakai S, Richter T, Pineau T, Alexander DL, Savas U et al. Cytochrome P450 CYP1B1 determines susceptibility to 7,12-dimethylbenz[a]anthracene-induced lymphomas Proc Natl Acad Sci USA 1999 96: 1977–1982

    Article  CAS  Google Scholar 

  47. Lee SST, Buters JTM, Pineau T, Fernandez-Salguero P, Gonzalez FJ . Role of CYP2E1 in the hepatotoxicity of acetaminophen J Biol Chem 1996 271: 12063–12067

    Article  CAS  Google Scholar 

  48. Valentine CR, Valentine JL, Seng J, Leakey J, Casciano D . The use of transgenic cell lines for evaluating toxic metabolites of carbamazepine Cell Biol Toxicol 1996 12: 155–165

    Article  CAS  Google Scholar 

  49. Raucy JL, Lasker JM, Lieber CS, Black M . Acetaminophen activation by human liver cytochromes P450IIE1 and P450IA2 Arch Biochem Biophys 1989 271: 270–283

    Article  CAS  Google Scholar 

  50. Zaher H, Buters JTM, Ward JM, Bruno MK, Lucas AM, Stern ST et al. Protection against acetaminophen toxicity in CYP1A2 and CYP2E1 double-null mice Toxicol Appl Pharmacol 1998 152: 193–199

    Article  CAS  Google Scholar 

  51. Shimizu Y, Nakatsuru Y, Ichinose M, Takahashi Y, Kume H, Mimura J et al. Benzo[a]pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor Proc Natl Acad Sci USA 2000 97: 779–782

    Article  CAS  Google Scholar 

  52. Fernandez-Salguero P, Pineau T, Hilbert DM, McPhail T, Lee S, Kimura S et al. Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor Science 1995 268: 722–726

    Article  CAS  Google Scholar 

  53. Gonzalez FJ, Fernandez-Salguero P . Anthony YH Lu commemorative issue. The aryl hydrocarbon receptor. Studies using the AhR-null mice Drug Metab Dispos 1998 26: 1194–1198

    CAS  PubMed  Google Scholar 

  54. Fernandez-Salguero P, Hilbert D, Rudikoff S, Ward J, Gonzalez FJ . Aryl-hydrocarbon receptor-deficient mice are resistant to 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity Toxicol Appl Pharmacol 1996 140: 173–179

    Article  CAS  Google Scholar 

  55. Lee SS, Gonzalez FJ . Targeted disruption of the peroxisome proliferator-activated receptor alpha gene, PPAR alpha Ann NY Acad Sci 1996 804: 524–529

    Article  CAS  Google Scholar 

  56. Leone TC, Weinheimer CJ, Kelly DP . A critical role for the peroxisome proliferator-activated receptor α (PPARα) in the cellular fasting response: the PPARα-null mouse as a model of fatty acid oxidation disorders Proc Natl Acad Sci USA 1999 96: 7473–7478

    Article  CAS  Google Scholar 

  57. Palmer CNA, Hsu MH, Griffin KJ, Raucy JL, Johnson EF . Peroxisome proliferator activated receptor-α expression in human liver Mol Pharmacol 1998 53: 14–22

    Article  CAS  Google Scholar 

  58. Kliewer SA, Moore JT, Wade L, Staudinger JL, Watson MA, Jones SA et al. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway Cell 1998 92: 73–82

    Article  CAS  Google Scholar 

  59. Synold TW, Dussault I, Forman BM . The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nat Med 2001 7: 584–590

    CAS  Google Scholar 

  60. Xie W, Barwick JL, Downes M, Blumberg B, Simon CM, Nelson MC et al. Humanized xenobiotic response in mice expressing nuclear receptor SXR Nature 2000 406: 435–439

    Article  CAS  Google Scholar 

  61. Xie W, Barwick J, Simon C, Pierce AM, Safe S, Blumberg B et al. Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR Genes Dev 2000 14: 3014–3023

    Article  CAS  Google Scholar 

  62. Ueno T, Tamura S, Frels WI, Shou M, Gonzalez FJ, Kimura S . A transgenic mouse expressing human CYP1A2 in the pancreas Biochem Pharmacol 2000 60: 857–863

    Article  CAS  Google Scholar 

  63. Imaoka S, Hayashi K, Hiroi T, Yabusaki Y, Kamataki T, Funae Y . A transgenic mouse expressing human CYP4B1 in the liver Biochem Biophys Res Commun 2001 284: 757–762

    Article  CAS  Google Scholar 

  64. Li Y, Yokoi T, Kitamura R, Sasaki M, Gunji M, Katsuki M et al. Establishment of transgenic mice carrying human fetus-specific CYP3A7 Arch Biochem Biophys 1996 329: 235–240

    Article  CAS  Google Scholar 

  65. Inui H, Kodama T, Ohkawa Y, Ohkawa H . Herbicide metabolism and cross-tolerance in transgenic potato plants co-expressing human CYP1A1, CYP2B6, and CYP2C19 Pestic Biochem Physiol 2000 66: 116–129

    Article  CAS  Google Scholar 

  66. Doty SL, Shang TQ, Wilson AM, Tangen J, Westergreen AD, Newman LA et al. Enhanced metabolism of halogenated hydrocarbons in transgenic plants containing mammalian cytochrome P450 2E1 Proc Natl Acad Sci USA 2000 97: 6287–6291

    Article  CAS  Google Scholar 

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Raucy, J., Allen, S. Recent advances in P450 research. Pharmacogenomics J 1, 178–186 (2001). https://doi.org/10.1038/sj.tpj.6500044

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