Analysis of differential substrate selectivities of CYP2B6 and CYP2E1 by site-directed mutagenesis and molecular modeling

Journal of Pharmacology and Experimental Therapeutics

Volumn 304, Issue 1, 2003, Pages 477-487

  Spatzenegger, Margit ^a   Liu, Hong ^a,c   Wang, Qinmi ^a   Debarber, Andrea ^b   Koop, Dennis R ^b   Halpert, James R ^a  

^a University of Texas Medical Branch School of Medicine   (United States)

^b OREGON HEALTH AND SCIENCE UNIVERSITY   (United States)

^c INSTITUTE OF GEOLOGY AND GEOPHYSICS   (China)

Author keywords

[No Author keywords available]

Indexed keywords

7 BUTOXYCOUMARIN; 7 ETHOXY 4 TRIFLUOROMETHYLCOUMARIN; 7 ETHOXYCOUMARIN; COUMARIN DERIVATIVE; CYTOCHROME P450 2B6; CYTOCHROME P450 2E1; MUTANT PROTEIN; UNCLASSIFIED DRUG;

AMINO ACID SUBSTITUTION; ARTICLE; CONTROLLED STUDY; CRYSTAL STRUCTURE; ENZYME ANALYSIS; ENZYME SPECIFICITY; ENZYME STRUCTURE; ENZYME SUBSTRATE; MOLECULAR MODEL; PRIORITY JOURNAL; SITE DIRECTED MUTAGENESIS;

AMINO ACID SEQUENCE; ARACHIDONIC ACID; ARYL HYDROCARBON HYDROXYLASES; BINDING SITES; COMPUTER SIMULATION; CYTOCHROME P-450 CYP2E1; DEALKYLATION; HUMANS; HYDROXYLATION; KINETICS; MODELS, MOLECULAR; MUTAGENESIS, SITE-DIRECTED; MUTATION; OLIGONUCLEOTIDE PROBES; OXIDATION-REDUCTION; OXIDOREDUCTASES, N-DEMETHYLATING; PROTEIN CONFORMATION; SUBSTRATE SPECIFICITY;

EID: 0037216623     PISSN: 00223565     EISSN: None     Source Type: Journal    
DOI: 10.1124/jpet.102.043323     Document Type: Article

References (40)

1. Adas F, Salaun JP, Berthou F, Picart D, Simon B, and Amet Y (1999) Requirement for ω and (ω-1)-hydroxylations of fatty acids by human cytochromes P450 2E1 and 4A11. J Lipid Res 40:1990-1997.
2. Afzelius L, Zamora I, Ridderström M, Andersson TB, Karlén A, and Masimirembwa CM (2001) Competitive CYP2C9 inhibitors: Enzyme inhibition studies, protein homology modeling and three-dimensional quantitative structure-activity relationship analysis. Mol Pharmacol 59:909-919.
3. Christ DD, Fiske WD, Grubb MF, Hazelette J, Finan WL, Massello BA, and Bilski DA (1997) The novel non-nucleoside reverse transcriptase inhibitor DMP 266 produces autoinduction of metabolism in rats and rhesus monkeys (Abstract). ISSX Proc 12:299.
4. Dai R, Pincus MR, and Friedman FK (1998) Molecular modeling of cytochrome P450 2B1: Mode of membrane insertion and substrate specificity. J Protein Chem 17:121-129.
5. Dicker E, McHugh T, and Cederbaum AI (1990) Increased oxidation ofp-nitrophenol and aniline by intact hepatocytes isolated from pyrazole-treated rats. Biochim Biophys Acta. 1035:249-256.
6. Domanski TL and Halpert JR (2001) Analysis of mammalian cytochrome P450 structure and function by site-directed mutagenesis. Curr Drug Metab. 2:117-137.
7. Domanski TL, He YQ, Scott EE, Wang Q, and Halpert JR (2001) The role of cytochrome 2B1 substrate recognition site residues 115, 294, 297, 298 and 362 in the oxidation of steroids and 7-alkoxycoumarins. Arch Biochem Biophys 394:21-28.
8. Domanski TL, Schultz KM, Roussel F, Stevens JC, and Halpert JR (1999) Structure-function analysis of human cytochrome P-450 2B6 using a novel substrate, site-directed mutagenesis and molecular modeling. J Pharmacol Exp Ther 290:1141-1147.
9. Faucette SR, Hawke RL, Lecluyse EL, Shord SS, Yan B, Laethem RM, and Lindley CM (2000) Validation of bupropion hydroxylation as a selective marker of human cytochrome P450 2B6 catalytic activity. Drug Metab Dispos 28:1222-1230.
10. Garton KJ, Yuen P, Meinwald J, Thummel KE, and Kharasch ED (1995) Stereoselective metabolism of enflurane by human liver cytochrome P450 2E1 Drug Metab. Dispos 23:1426-1430.
11. Goldstein JA and de Morais SM (1994) Biochemistry and molecular biology of the human CYP2C subfamily. Pharmacogenetics 4:285-299.
12. Harlow GR, He YA, and Halpert JR (1997) Functional interaction between aminoacid residues 242 and 290 in cytochromes P-450 2B1 and 2B11. Biochim Biophys Acta. 1338:259-266.
13. He Y, Szklarz GD, and Halpert JR (1996) Interconversion of the androstenedione hydroxylase specificities of cytochromes P450 2B4 and 2B5 upon simultaneous site-directed mutagenesis of four key substrate recognition residues. Arch Biochem Biophys 335:152-160.
14. He YQ, He YA, and Halpert JR (1995) Escherichia coli expression of site-directed mutants of cytochrome P450 2B1 from six substrate recognition sites: Substrate specificity and inhibitor selectivity studies. Chem Res Toxicol 8:574-579.
15. Heyn H, White RB, and Stevens JC (1996) Catalytic role of cytochrome P4502B6 in the N-demethylation of S-mephenytoin. Drug Metab Dispos 24:948-954.
16. Kim H, Wang RS, Elovaara E, Raunio H, Pelkonen O, Aoyama T, Vainio H, and Nakajima T (1997) Cytochrome P450 isozymes responsible for the metabolism of toluene and styrene in human liver microsomes. Xenobiotica 27:657-665.
17. Kobayashi Y, Fang X, Szklarz GD, and Halpert JR (1998) Probing the active site of cytochrome P450 2B1: Metabolism of 7-alkoxycoumarins by the wild type and five site-directed mutants. Biochemistry 37:6679-6688.
18. Koop DR (1992) Oxidative and reductive metabolism by cytochrome P450 2E1. FASEB J 6:724-730.
19. Koop DR, Laethem CL, and Tierney DJ (1989) The utility of p-nitrophenol hydroxylation in P450IIE1 analysis. Drug Metab Rev 20:541-551.
20. Laethem RM, Balazy M, Falck JR, Laethem CL, and Koop DR (1993) Formation of 19(S)-, 19(R)- and 18(R)-hydroxyeicosatetraenoic acids by alcohol-inducible cytochrome P450 2E 1. J Biol Chem 268:12912-12918.
21. Luo Z, He YA, and Halpert JR (1994) Role of residues 363 and 206 in conversion of cytochrome P450 2B1 from a steroid 16-hydroxylase to a 15Α-hydroxylase. Arch Biochem Biophys 309:52-57.
22. Mackman R, Guo Z, Guengerich FP, and Ortiz de Montellano PR (1996) Active site topology of human cytochrome P450 2El. Chem Res Toxicol. 9:223-226.
23. Moreno RL, Goosen T, Kent UM, Chung FL, and Hollenberg PF (2001) Differential effects of naturally occurring isothiocyanates on the activities of cytochrome P450 2El and the mutant P450 2E1 T303A. Arch Biochem Biophys 391:99-110.
24. Negishi M, Uno T, Honkakoski P, Sueyoshi T, Darden T, and Pedersen LP (1996) The roles of individual amino acids in altering substrate specificity of the P450 2a4/2a5 enzymes. Biochimie (Paris) 78:685-694.
25. Omura T and Sato R (1964) The carbon monoxide-binding pigment of liver microsomes. J Biol Chem 239:2379-2387.
26. cam. Proteins 11:184-204.
27. cam. J Comput-Aided Mol Des 6:235-252.
28. Rendic S and Di Carlo FJ (1997) Human cytochrome P450 enzymes: A status report summarizing their reactions, substrates, inducers and inhibitors. Drug Metab Rev 29:413-580.
29. Riska P, Lamson M, MacGregor T, Sabo J, Hattox S, Pav J, and Keirns J (1999) Disposition and biotransformation of the antiretroviral drug nevirapine in humans. Drug Metab Dispos 27:895-901.
30. Roy P, Yu LJ, Crespi CL, and Waxman DJ (1999) Development of a substrate-activity based approach to identify the major human liver P-450 catalysts of cyclophosphamide and ifosfamide activation based on cDNA-expressed activities and liver microsomal P-450 profiles. Drug Metab Dispos 27:655-666.
31. Scott EE, Spatzenegger M, and Halpert JR (2001) A truncation of 2B subfamily cytochromes P450 yields increased expression levels, increased solubility and decreased aggregation while retaining function. Arch Biochem Biophys 395:57-68.
32. Shenkin PS, Yarmush DL, Fine RM, Wang H, and Levinthal C (1987) Predicting antibody hypervariable loop conformation. I. Ensembles of random conformations for ringlike structures. Biopolymers 26:2053-2085.
33. Smith SV, Koley AP, Dai R, Robinson RC, Leong H, Markowitz A, and Friedman FK (2000) Conformational modulation of human cytochrome P450 2E1 by ethanol and other substrates: A CO flash photolysis study. Biochemistry 39:5731-5737.
34. Spatzenegger M, Wang Q, He YQ, Wester MR, Johnson EF, and Halpert JR (2001) Amino acid residues critical for differential inhibition of CYP2B4, CYP2B5 and CYP2B1 by phenylimidazoles. Mol Pharmacol 59:475-485.
35. Stresser DM and Kupfer D (1999) Monospecific antipeptide antibody to cytochrome P-450 2B6. Drug Metab Dispos 27:517-525.
36. Szklarz GD, He YA, and Halpert JR (1995) Site-directed mutagenesis as a tool for molecular modeling of cytochrome P450 2B1. Biochemistry 34:14312-14322.
37. Wang M-H, Wade D, Chen L, White S, and Yang CS (1995) Probing the active sites of rat and human cytochrome P450 2E1 with alcohols and carboxylic acids. Arch Biochem Biophys 317:299-304.
38. Wang QM and Halpert JR (2002) Combined three-dimensional quantitative structure-activity relationship analysis of cytochrome P450 2B6 substrates and protein homology modeling. Drug Metab Dispos 30:86-95.
39. Waterman MR, Jenkins CM, and Pikuleva I (1995) Genetically engineered bacterial cells and applications. Toxicol Letters 82-83:807-813.
40. Williams PA, Cosme J, Sridhar V, Johnson EF, and McRee DE (2000) Microsomal cytochrome P450 2C5: Comparison to microbial P450s and unique features. J Inorg Biochem 81:183-190.