Investigation of enzyme selectivity in the human CYP2C subfamily: Homology modelling of CYP2C8, CYP2C9 and CYP2C19 from the CYP2C5 crystallographic template

Drug Metabolism and Drug Interactions

Volumn 19, Issue 4, 2003, Pages 257-285

  Lewis, David F V ^a   Dickins, Maurice ^b   Lake, Brian G ^c   Goldfarb, Peter S ^a  

^a UNIVERSITY OF SURREY   (United Kingdom)

^b PFIZER GLOBAL RESEARCH AND DEVELOPMENT   (United Kingdom)

^c BIBRA INTERNATIONAL   (United Kingdom)

Author keywords

CYP2C5 structural template; Cytochrome P450; Homology modelling; Human CYP2C; Xenobiotic metabolism and activation

Indexed keywords

2 (4 TERT BUTYLCYCLOHEXYL) 3 HYDROXY 1,4 NAPHTHOQUINONE; ARACHIDONIC ACID; CARBAMAZEPINE; CERIVASTATIN; CYTOCHROME P450 2C; CYTOCHROME P450 2C19; CYTOCHROME P450 2C5; CYTOCHROME P450 2C8; CYTOCHROME P450 2C9; DICLOFENAC; HEXOBARBITAL; IBUPROFEN; LY 307640; MEFENAMIC ACID; METHYLPHENOBARBITAL; MOCLOBEMIDE; NAPROXEN; PACLITAXEL; PHENYTOIN; PIROXICAM; RABEPRAZOLE; RETINOIC ACID; RETINOL; ROSIGLITAZONE; TIENILIC ACID; TOLBUTAMIDE; TRIMETHOPRIM; UNCLASSIFIED DRUG; UNINDEXED DRUG; WARFARIN; ZOPICLONE;

AMINO ACID SEQUENCE; ARTICLE; CATALYST; CORRELATION COEFFICIENT; CRYSTAL STRUCTURE; CRYSTALLOGRAPHY; DRUG METABOLISM; ENZYME ACTIVE SITE; ENZYME SPECIFICITY; ENZYME STRUCTURE; ENZYME SUBSTRATE COMPLEX; HUMAN; PKA; QUANTITATIVE STRUCTURE ACTIVITY RELATION; SEQUENCE ANALYSIS; SEQUENCE HOMOLOGY; SITE DIRECTED MUTAGENESIS; XENOBIOTIC METABOLISM;

EID: 1642446616     PISSN: 07925077     EISSN: None     Source Type: Journal    
DOI: 10.1515/DMDI.2003.19.4.257     Document Type: Article

References (74)

1. Anzenbacher P, Anzenbacherova E. Cytochromes P450 and metabolism of xenobiotics. Cell Mol Life Sci 2001; 58: 737-747.
2. Lewis DFV. Guide to Cytochromes P450 Structure and Function. London: Taylor & Francis, 2001.
3. Nelson DR. Metazoan cytochrome P450 evolution. Comp Biochem Physiol C 1998; 121: 15-22.
4. Lewis DFV. Cytochromes P450: Structure, Function and Mechanism. London: Taylor & Francis, 1996.
5. Rendic S, DiCarlo FJ. Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers and inhibitors. Drug Metab Rev 1997; 29: 413-580.
6. Evans WE, Relling MV. Pharmacogenomics: translating functional genomics into rational therapies. Science 1999; 286: 487-491.
7. Ingelman-Sundberg M, Oscarson M, McLellan RA. Polymorphic human cyto-chrome P450 enzymes: an opportunity for individualized drug treatment. Trends Pharmaceut Sci 1999; 20: 342-349.
8. Goldstein JA, de Morais SMF. Biochemistry and molecular biology of the human CYP2C subfamily. Pharmacogenetics 1994; 4: 285-299.
9. Richardson TH, Johnson EF. The CYP2C subfamily. In: Ioannides C, ed. Cytochromes P450 - Metabolic and Toxicological Aspects, Ch 7. Boca Raton, FL: CRC Press, 1996; 161-181.
10. Williams PA, Cosme J, Sridhar V, Johnson EF, McRee DE. Mammalian cytochrome P450 monooxygenase: structural adaptations for membrane binding and functional diversity. Mol Cell 2000; 5: 121-131.
11. Lewis DFV. Homology modelling of human CYP2 family enzymes based on the CYP2C5 crystal structure. Xenobiotica 2002; 32: 305-323.
12. Lewis DFV, Lake BG. Species differences in coumarin metabolism: a molecular modelling evaluation of CYP2A interactions. Xenobiotica 2002; 32: 547-561.
13. Lewis DFV, Dickins M, Weaver RJ, Eddershaw PJ, Goldfarb PS, Tarbit MH. Molecular modelling of human CYP2C subfamily enzymes CYP2C9 and CYP2C19: rationalization of substrate specificity and site-directed mutagenesis experiments in the CYP2C subfamily. Xenobiotica 1998; 28: 235-268.
14. Hansch C, Leo A, Hoekman D. Exploring QSAR: Hydrophobic, Electronic and Steric Constants. Washington, DC: American Chemical Society, 1995.
15. Dollery C. Therapeutic Drugs. Edinburgh: Churchill-Livingstone, 1999.
16. Haining RL, Jones JP, Henne KR, Fisher MB, Koop DR. Enzymatic determinants of the substrate specificity of CYP2C9: role of B-C loop residues in providing the pi-stacking anchor site for warfarin binding. Biochemistry 1999; 38: 3285-3292.
17. Haining RL, Hunter AP, Veronese E, Trager WF, Rettie AE. Allelic variants of human cytochrome P450 2C9: baculovirus-mediated expression, purification, structural characterization, substrate stereoselectivity and prochiral selectivity of the wild-type and 1359L mutant forms. Arch Biochem Biophysics. 1996; 333: 447-458.
18. 359 variants: enzyme kinetic study with seven substrates. Pharmacogenetics 2000; 10: 95-104.
19. Ibeanu GS, Ghanayem BI, Linko P, Li L, Pedersen LG, Goldstein JA. Identification of residues 99, 220 and 221 of human cytochrome P450 2C19 as key determinants of omeprazole hydroxylase activity. J Biol Chem 1996; 271: 12496-12501.
20. Tsao C-C, Wester MR, Ghanayem B, Coulter SJ, Chanas B, Johnson EF, Goldstein JA. Identification of human CYP2C19 residues that confer S-mephenytoin 4′-hydroxylation activity to CYP2C9. Biochemistry 2001; 40: 1937-1944.
21. Lewis DFV. On the recognition of mammalian microsomal cytochrome P450 substrates and their characteristics. Biochem Pharmacol 2000; 60: 293-306.
22. Lewis DFV. The CYP2 family: models, mutants and interactions. Xenobiotica 1998; 28: 617-661.
23. Smith DA, Jones BC. Speculations on the substrate structure-activity relationship (SSAR) of cytochrome P450 enzymes. Biochem Pharmacol 1992; 44: 2089-2098.
24. Baldwin SJ, Clarke SE, Chenery RJ. Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of rosiglitazone. Br J Clin Pharmacol 1999; 48: 424-432.
25. Mancy A, Broto P, Dijols S, Dansette PM, Mansuy D. The substrate binding site of human liver cytochrome P450 2C9: an approach using tienilic acid derivatives and molecular modeling. Biochemistry 1995; 34: 10365-10375.
26. He M, Kunze KL, Trager WF. Inhibition of S-warfarin metabolism by sulfinpyrazone and its metabolites. Drug Metab Dispos 1995; 23: 659-663.
27. Miners JO, Birkett DJ. Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Phannacol 1998; 45: 525-538.
28. Weinkers LC, Wurden CJ, Storch E, Kunze KL, Rettie AE, Trager WF. Formation of (R)-8-hydroxywarfarin in human liver microsomes. Drug Metab Dispos 1996; 24: 610-614.
29. Marill J, Cresteil T, Lanotte M, Chabot GG. Identification of human cytochrome P450s involved in the formation of all-trans-retinoic acid principal inetabolites. Mol Pharmacol 2000; 58: 1341-1348.
30. Marill J, Capron CC, Idres N, Chabot GG. Human cytochrome P450s involved in the metabolism of 9-cis- and 13-cis-retoinoic acids. Biochem Pharmacol 2002; 63: 937-947.
31. Leo MA, Lasker JM, Raucy JL, Kim C-I, Black M, Lieber CS. Metabolism of retinol and retinoic acid by human liver cytochrome P45011C8. Arch Biochem Biophys 1989; 269: 305-312.
32. Crespi CL, Chang TKH, Waxman DJ. High-performance liquid chromatographic analysis of CYP2C8-catalyzed paclitaxel 6α-hydroxylation. In: Phillips IR, Shephard EA, eds. Cytochrome P450 Protocols. Totowa, NJ: Humana Press, 1998; 123-127.
33. Kerr BM, Thummel KE, Wurden CJ, Klein SM, Kroetz DL, Gonzalez FJ, Levy RH. Human liver carbamazepine metabolism: role of CYP3A4 and CYP2C8 in 10,11-epoxide formation. Biochem Pharmacol 1994; 47: 1969-1979.
34. Becquemont L, Mouajjah S, Escaffre O, Beaune P, Funck-Brentano C, Jaillon P. Cytochrome P450 3A4 and 2C8 are involved in zopiclone metabolism. Drug Metab Dispos 1999; 27: 1068-1073.
35. White INH, Green ML, Legg RF. Fluorescence-activated sorting of rat hepatocytes based on their mixed function oxidase activities towards fluorescein. Biochem J 1987; 247: 23-28.
36. Mück W, Ochmana K, Rohde G, Unger S, Kuhlmann J. Influence of erythromycin pre- and co-treatment on single dose pharmacokinetics of the HMG-CoA reductase inhibitor cerivastatin. Eur J Clin Pharmacokinet 1998; 53: 469-473.
37. Ohyama K, Nakajima M, Nakamura S, Shimada N, Yamazaki H, Yokoi T. A significant role of human cytochrome P450 2C8 in amiodarone N-deethylation: an approach to predict the contribution with relative activity factor. Drug Metab Dispos 2000; 28: 1303-1310.
38. TB (CYP2C) controls mefenamic acid elimination. Clin Pharmacol Therap 1994; 55: 139.
39. Miners JO, Coulter S, Tukey RH, Veronese ME, Birkett DJ. Cytochromes P450 1A2 and 2C9 are responsible for the human hepatic O-demethylation of R- and S-naproxen. Biochem Pharmacol 1996; 51: 1003-1008.
40. Weaver RJ, Dickins M, Burke MD. Cytochrome P4502C9 is responsible for hydroxylation of the naphthoquinone antimalarial drug 58C80 in human liver. Biochem Pharmacol 1993; 46: 1183-1197.
41. TB (CYP2C subfamily) in the actions of non-steroidal anti-inflammatory drugs. Drugs Exp Clin Res 1993; 19: 189-195.
42. Stearns RA, Chakravarty PK, Chen R, Lee Chiu S-H. Biotransformation of losartan to its active carboxylic acid metabolite in human liver microsomes. Drug Metab Dispos 1995; 23: 207-215.
43. Andersson T, Miners JO, Veronese ME, Tassaneeyakul W, Tassaneeyakul W, Meyer UA, Birkett DJ. Identification of human liver cytochrome P450 isoforms mediating omeprazole metabolism. Br J Clin Pharmacol 1993; 36: 521-530.
44. Hall SD, Guengerich FP, Branch RA, Wilkinson GR. Characterization and inhibition of mephenytoin 4-hydroxylase activity in human liver microsomes. J Pharmacol Exp Ther 1987; 240: 216-222.
45. Birkett DJ, Rees D, Andersson T, Gonzalez FJ, Miners JO, Veronese ME. In vitro proguanil activation to cycloguanil by human liver microsomes is mediated by CYP3A isoforms as well as by 3-mephenytoin hydroxylase. Br J Clin Pharmacol 1994; 37: 413-420.
46. McGinnity DF, Griffin SJ, Moody GC, Voice M, Hanlon S, Friedberg T, Riley RJ. Rapid characterization of the major drug-metabolizing human hepatic cytochrome P450 enzymes expressed in Escherichia coli. Drug Metab Dispos 1999; 27: 1017-1023.
47. Bajpai M, Roskos LK, Shen DD, Levy RH. Roles of cytochrome P4502C9 and cytochrome P4502C19 in the stereoselective metabolism of phenytoin to its major metabolite. Drug Metab Dispos 1996; 24: 1401-1403.
48. Knodell RG, Dubey RK, Wilkinson GR, Guengerich FP. Oxidative metabolism of hexobarbital in human liver: relationship to polymorphic S-mephellytoin oxidation. J Pharmacol Exp Ther 1988; 245: 845-849.
49. Kobayashi K, Kogo M, Tani M, Shimada N, Ishizaki T, Numazawa S, Yoshida T, Yamamoto T, Kuroiwa Y, Chiba K. Role of CYP2C19 in stereo-selective hydroxylation of mephobarbital by human liver microsomes. Drug Metab Dispos 2001; 29: 36-40.
50. Hoskins J, Shenfield G, Murray M, Gross A. Characterization of moclobemide N-oxidation in human liver microsomes. Xenobiotica 2001; 31: 387-397.
51. Facciola G, Hidestrand M, von Bahr C, Tybring G. Cytochrome P450 isoforms involved in melatonin metabolism in human liver microsomes. Eur J Clin Pharmacol 2001; 56: 881-888.
52. VandenBranden M, Ring BJ, Binkley SN, Wrighton SA. Interaction of human liver cytochromes P450 in vitro with LY307640, a gastric proton pump inhibitor. Pharmacogenetics 1996; 6: 81-91.
53. Yamazaki S, Sato K, Suhaka K, Sakaguchi M, Mihara K, Oinura T. Importance of the proline-rich region following signal-anchor sequence in the formation of correct conformation of microsomal cytochrome P450s. J Biochem 1993; 114: 652-657.
54. Chen C-D, Kemper B. Different structural requirements at specific proline residue positions in the conserved proline-rich region of cytochrome P450 2C2. J Biol Chem 1996; 271: 28607-28611.
55. Ridderström M, Masimirembara C, Trump-Kallmeyer S, Ahlefelt M, Otter C, Andersson TB. Arginines 97 and 108 in CYP2C9 are important determinants of the catalytic function. Biochem Biophys Res Commun 2000; 270: 983-987.
56. Straub P, Lloyd M, Johnson EF, Kemper B. Cassette mutagenesis of a potential substrate recognition region of cytochrome P450 2C2. J Biol Chem 1993; 268: 21997-22003.
57. Richardson TH, Johnson EF. Alterations of the regiospecificity of progesterone metabolism by the mutagenesis of two key amino acid residues in rabbit cytochrome P450 2C3v. J Biol Chem 1994; 269: 23927-23943.
58. Tracy TS, Hutzler JM, Haining RL, Rettie AE, Hummel MA, Dickmann LJ. Polymorphic variants (CYP2C9*3 and CYP2C9*5) and the F114L active site mutation of CYP2C9: effect on atypical kinetic metabolism profiles. Drug Metab Dispos 2002; 30: 385-390.
59. Kronbach T, Larabee TM, Johnson EF. Hybrid cytochromes P450 identify a substrate binding domain in P450IIC5 and P450IIC4. Proc Natl Acad Sci USA 1989; 86: 8262-8265.
60. Kaminsky LS, de Morais SMF, Faletto MB, Dunbar DA, Goldstein JA. Correlation of human cytochrome P4502C substrate specificities with primary structure: warfarin as a probe. Mol Pharmacol 1993; 43: 234-239.
61. Hsu M-H, Griffin KJ, Wang Y, Kemper B, Johnson EF. A single amino acid substitution confers progesterone 6-hydroxylase activity to rabbit cytochrome P450 2C3. J Biol Chem 1993; 268: 6939-6944.
62. 180Cys determines the polymorphism in cytochrome P450g (P4502C13) by altering protein stability. J Biol Chem 1992; 267: 2032-2037.
63. Jung F, Griffin KJ, Song W, Richardson TH, Yang M, Johnson EF. Identification of amino acid substitutions that confer a high affinity for sulfaphenazole binding and a high catalytic efficiency for warfarin metabolism to P450 2C19. Biochemistry 1998; 37: 16270-16279.
64. Ohgiya S, Komori M, Ohi H, Shiramatsu K, Shinriki N, Kamataki T. Six-base deletion occurring in messages of human cytochrome P450 in the CYP2C subfamily results in reduction of tolbutamide hydroxylase activity. Biochem Int 1992; 27: 1073-1081.
65. Klose TS, Ibeanu GC, Ghanayem BI, Pedersen LG, Li L, Hall SD, Goldstein JA. Identification of residues 286 and 289 as critical for conferring substrate specificity of human CYP2C9 for diclofenac and ibuprofen. Arch Biochem Biophys 1998; 357: 240-248.
66. Imai Y, Nakamura M. Point mutations at threonine-301 modify substrate specificity of rabbit liver microsomal cytochromes P450 laurate (ω-1)-hydroxylase and testosterone 16α-hydroxylase. Biochem Biophys Res Commun 1989; 158: 717-722.
67. Afzelius L, Zamora I, Ridderström M, Andersson TB, Karlen A, Masimirembwa CW. Competitive CYP2C9 inhibitors: enzyme inhibition studies, protein homology modeling and three-dimensional quantitative structure-activity relationship analysis. Mol Pharmacol 2001; 59: 909-919.
68. Ramarao MK, Straub P, Kemper B. Identification by in vitro mutagenesis of the interaction of two segments of C2MstC1, a chimera of cytochromes P450 2C2 and P450 2C1. J Biol Chem 1995; 270: 1873-1880.
69. Veronese ME, Doecke CJ, Mackenzie PI, McManus ME, Miners JO, Rees DLP, Gasser R, Meyer UA, Birkett DJ. Site-directed mutation studies of human liver cytochrome P450 enzymes in the CYP2C subfamily. Biochem J 1993; 289: 533-538.
70. Uno T, Imai Y, Nakamura M, Okamoto N, Fukuda T. Importance of successive prolines in the carboxy-terminal region of P450 2C2 and P450 2C 14 for the hydroxylase activities. J Biochem 1993; 114: 363-369.
71. Von Wachenfeldt C, Johnson EF. Structures of eukaryotic cytochrome P450 enzymes. In: Ortiz de Montellano PR., ed. Cytochrome P450. New York: Plenum Press, 1995; 183-223.
72. Gotoh O. Substrate recognition sites in cytochrome P450 family 2 (CYP2) proteins inferred from comparative analysis of amino acid and coding nucleotide sequences. J Biol Chem 1992; 267: 83-90.
73. Lewis DFV, Bailey PT, Low LK. Molecular modelling of the mouse cytochrome P450 CYP2F2 based on the CYP102 crystal structure template and selective CYP2F2 substrate interactions. Drug Metab Drug Interact 2002; 19: 97-113.
74. Lewis DFV, Lake BG, Dickins M, Goldfarb PS. Molecular modelling of CYP2B6 based on homology with the CYP2C5 crystal structure: analysis of enzyme-substrate interactions. Drug Metab Drug Interact 2002; 19: 115-135.