Novel CYP2B6 Enzyme Variants in a Rwandese Population: Functional Characterization and Assessment of In Silico Prediction Tools

Human Mutation

Volumn 34, Issue 5, 2013, Pages 725-734

  Radloff, Robert ^a   Gras, Alain ^b   Zanger, Ulrich M ^a   Masquelier, Cécile ^b   Arumugam, Karthik ^b   Karasi, Jean Claude ^c   Arendt, Vic ^d   Seguin Devaux, Carole ^b   Klein, Kathrin ^a  

^a UNIVERSITY OF TÜBINGEN   (Germany)

^b LUXEMBOURG INSTITUTE OF HEALTH   (Luxembourg)

^c Rwandese Biomedical Center at Kigali   (Rwanda)

^d CENTRE HOSPITALIER DE LUXEMBOURG   (Luxembourg)

Author keywords

CYP2B6; Cytochrome P450; Docking; Efavirenz; Molecular dynamics

Indexed keywords

AMFEBUTAMONE; CYTOCHROME P450 2B6; EFAVIRENZ; ENZYME VARIANT; PESTICIDE;

ALGORITHM; ALLELE; ARTICLE; CONFORMATIONAL TRANSITION; DRUG HYDROXYLATION; ENZYME ACTIVE SITE; ENZYME ACTIVITY; GENE MUTATION; GENETIC ASSOCIATION; HAPLOTYPE; HUMAN; LIGAND BINDING; LOSS OF FUNCTION MUTATION; MOLECULAR DOCKING; MOLECULAR DYNAMICS; MUTAGENESIS; NUCLEOTIDE SEQUENCE; PHENOTYPE; PRIORITY JOURNAL; PROTEIN SECONDARY STRUCTURE; RWANDA; SEQUENCE ANALYSIS; SIMULATION; SINGLE NUCLEOTIDE POLYMORPHISM; VERTICAL TRANSMISSION; WESTERN BLOTTING;

ARYL HYDROCARBON HYDROXYLASES; BLOTTING, WESTERN; GENETICS, POPULATION; HAPLOTYPES; HUMANS; MOLECULAR DYNAMICS SIMULATION; MUTATION; OXIDOREDUCTASES, N-DEMETHYLATING; POLYMORPHISM, SINGLE NUCLEOTIDE; RWANDA;

EID: 84876313111     PISSN: 10597794     EISSN: 10981004     Source Type: Journal    
DOI: 10.1002/humu.22295     Document Type: Article

References (56)

1. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR. 2010. A method and server for predicting damaging missense mutations. Nat Methods 7:248-249.
2. Altschul SF, Madden TL, Schäffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ. 1997. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res 25:3389-3402.
3. Bairoch A, Apweiler R. 1997. The SWISS-PROT protein sequence database: its relevance to human molecular medical research. J Mol Med 75:312-316.
4. Bromberg Y, Rost B. 2007. SNAP: predict effect of non-synonymous polymorphisms on function. Nucleic Acids Res 35:3823-3835.
5. Brooks B, Brucceleri R, Olafson B, States D, Swaminathan S, Karplus M. 1983. CHARMM: a program for macromolecular energy, minimization, and dynamics calculations. 4:187-217.
6. Calabrese R, Capriotti E, Fariselli P, Martelli PL, Casadio R. 2009. Functional annotations improve the predictive score of human disease-related mutations in proteins. Hum Mutat 30:1237-1244.
7. Capriotti E, Calabrese R, Casadio R. 2006. Predicting the insurgence of human genetic diseases associated to single point protein mutations with support vector machines and evolutionary information. Bioinformatics 22:2729-2734.
8. Crane AL, Klein K, Olson JR. 2012. Bioactivation of chlorpyrifos by CYP2B6 variants. Xenobiotica 42:1255-1262.
9. Desta Z, Saussele T, Ward B, Blievernicht J, Li L, Klein K, Flockhart DA, Zanger UM. 2007. Impact of CYP2B6 polymorphism on hepatic efavirenz metabolism in vitro. Pharmacogenomics 8:547-558.
10. Faucette SR, Hawke RL, Lecluyse EL, Shord SS, Yan B, Laethem RM, Lindley CM. 2000. Validation of bupropion hydroxylation as a selective marker of human cytochrome P450 2B6 catalytic activity. Drug Metab Dispos 28:1222-1230.
11. Foxenberg RJ, McGarrigle BP, Knaak JB, Kostyniak PJ, Olson JR. 2007. Human hepatic cytochrome P450-specific metabolism of parathion and chlorpyrifos. Drug Metab Dispos 35:189-193.
12. Frishman D, Argos P. 1995. Knowledge-based protein secondary structure assignment. Proteins 23:566-579.
13. Gatanaga H, Hayashida T, Tsuchiya K, Yoshino M, Kuwahara T, Tsukada H, Fujimoto K, Sato I, Ueda M, Horiba M, Hamaguchi M, Yamamoto M, et al. 2007. Successful efavirenz dose reduction in HIV type 1-infected individuals with cytochrome P450 2B6 *6 and *26. Clin Infect Dis 45:1230-1237.
14. Gay SC, Shah MB, Talakad JC, Maekawa K, Roberts AG, Wilderman PR, Sun L, Yang JY, Huelga SC, Hong W-X, Zhang Q, Stout CD, et al. 2010. Crystal structure of a cytochrome P450 2B6 genetic variant in complex with the inhibitor 4-(4-chlorophenyl)imidazole at 2.0-Å resolution. Mol Pharmacol 77:529-538.
15. Gervot L, Rochat B, Gautier JC, Bohnenstengel F, Kroemer H, Berardinis V de, Martin H, Beaune P, Waziers I de. 1999. Human CYP2B6: expression, inducibility and catalytic activities. Pharmacogenetics 9:295-306.
16. Gotoh O. 1992. Substrate recognition sites in cytochrome P450 family 2 (CYP2) proteins inferred from comparative analyses of amino acid and coding nucleotide sequences. J Biol Chem 267:83-90.
17. Haas DW, Ribaudo HJ, Kim RB, Tierney C, Wilkinson GR, Gulick RM, Clifford DB, Hulgan T, Marzolini C, Acosta EP. 2004. Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study. AIDS 18:2391-2400.
18. Hesse LM, He P, Krishnaswamy S, Hao Q, Hogan K, Moltke LL von, Greenblatt DJ, Court MH. 2004. Pharmacogenetic determinants of interindividual variability in bupropion hydroxylation by cytochrome P450 2B6 in human liver microsomes. Pharmacogenetics 14:225-238.
19. Hiratsuka M. 2012. In vitro assessment of the allelic variants of cytochrome p450. Drug Metab Pharmacokin 27:68-84.
20. Hodgson E, Rose RL. 2007. The importance of cytochrome P450 2B6 in the human metabolism of environmental chemicals. Pharmacol Ther 113:420-428.
21. Hofmann MH, Blievernicht JK, Klein K, Saussele T, Schaeffeler E, Schwab M, Zanger UM. 2008. Aberrant splicing caused by single nucleotide polymorphism c.516G>T [Q172H], a marker of CYP2B6*6, is responsible for decreased expression and activity of CYP2B6 in liver. J Pharmacol Exp Ther 325:284-292.
22. Humphrey W, Dalke A, Schulten K. 1996. VMD: visual molecular dynamics. J Mol Graphics 14:33-38, 27-28.
23. Jamshidi Y, Moreton M, McKeown DA, Andrews S, Nithiyananthan T, Tinworth L, Holt DW, Sadiq ST. 2010. Tribal ethnicity and CYP2B6 genetics in Ugandan and Zimbabwean populations in the UK: implications for efavirenz dosing in HIV infection. J Antimicrob Chemother 65:2614-2619.
24. Klein K, Lang T, Saussele T, Barbosa-Sicard E, Schunck W-H, Eichelbaum M, Schwab M, Zanger UM. 2005. Genetic variability of CYP2B6 in populations of African and Asian origin: allele frequencies, novel functional variants, and possible implications for anti-HIV therapy with efavirenz. Pharmacogenet Genomics 15:861-873.
25. Kumar P, Henikoff S, Ng PC. 2009. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4:1073-1081.
26. Lang T, Klein K, Fischer J, Nüssler AK, Neuhaus P, Hofmann U, Eichelbaum M, Schwab M, Zanger UM. 2001. Extensive genetic polymorphism in the human CYP2B6 gene with impact on expression and function in human liver. Pharmacogenetics 11:399-415.
27. Lang T, Klein K, Richter T, Zibat A, Kerb R, Eichelbaum M, Schwab M, Zanger UM. 2004. Multiple novel nonsynonymous CYP2B6 gene polymorphisms in Caucasians: demonstration of phenotypic null alleles. J Pharmacol Exp Ther 311:34-43.
28. Li B, Krishnan VG, Mort ME, Xin F, Kamati KK, Cooper DN, Mooney SD, Radivojac P. 2009. Automated inference of molecular mechanisms of disease from amino acid substitutions. Bioinformatics 25:2744-2750.
29. Masquelier C, Servais J-Y, Rusanganwa E, Roman F, Havuga E, Servais J, Tuyizere S, Omes C, Karasi J-C, Coruteille O, Karita E, Allen S, et al. 2007. A novel 24-base pair deletion in the coding region of CCR5 in an African population. AIDS 21:111-113.
30. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ. 2009. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30:2785-2791.
31. Nguyen T-A, Tychopoulos M, Bichat F, Zimmermann C, Flinois J-P, Diry M, Ahlberg E, Delaforge M, Corcos L, Beaune P, Dansette P, André F, et al. 2008. Improvement of cyclophosphamide activation by CYP2B6 mutants: from in silico to ex vivo. Mol Pharmacol 73:1122-1133.
32. Nishikawa K, Ishino S, Takenaka H, Norioka N, Hirai T, Yao T, Seto Y. 1994. Constructing a protein mutant database. Protein Eng 7:733.
33. Niu R-J, Zheng Q-C, Zhang J-L, Zhang H-X. 2011. Analysis of clinically relevant substrates of CYP2B6 enzyme by computational methods. J Mol Model 17:2839-2846.
34. Ohtsuki S, Schaefer O, Kawakami H, Inoue T, Liehner S, Saito A, Ishiguro N, Kishimoto W, Ludwig-Schwellinger E, Ebner T, Terasaki T. 2012. Simultaneous absolute protein quantification of transporters, cytochromes P450, and UDP-glucuronosyltransferases as a novel approach for the characterization of individual human liver: comparison with mRNA levels and activities. Drug Metab Dispos 40:83-92.
35. Raska P, Zhu X. 2011. Rare variant density across the genome and across populations. BMC Proc 5:S39.
36. Ribaudo HJ, Liu H, Schwab M, Schaeffeler E, Eichelbaum M, Motsinger-Reif AA, Ritchie MD, Zanger UM, Acosta EP, Morse GD, Gulick RM, Robbins GK, et al. 2010. Effect of CYP2B6, ABCB1, and CYP3A5 polymorphisms on efavirenz pharmacokinetics and treatment response: an AIDS Clinical Trials Group study. J Infect Dis 202:717-722.
37. Richter T, Mürdter TE, Heinkele G, Pleiss J, Tatzel S, Schwab M, Eichelbaum M, Zanger UM. 2004. Potent mechanism-based inhibition of human CYP2B6 by clopidogrel and ticlopidine. J Pharmacol Exp Ther 308:189-197.
38. Rodriguez-Novoa S, Barreiro P, Rendón A, Jiménez-Nacher I, González-Lahoz J, Soriano V. 2005. Influence of 516G>T polymorphisms at the gene encoding the CYP450-2B6 isoenzyme on efavirenz plasma concentrations in HIV-infected subjects. Clin Infect Dis 40:1358-1361.
39. Rotger M, Tegude H, Colombo S, Cavassini M, Furrer H, Décosterd L, Blievernicht J, Saussele T, Günthard HF, Schwab M, Eichelbaum M, Telenti A, et al. 2007. Predictive value of known and novel alleles of CYP2B6 for efavirenz plasma concentrations in HIV-infected individuals. Clin Pharmacol Ther 81:557-566.
40. Saunders CT, Baker D. 2002. Evaluation of structural and evolutionary contributions to deleterious mutation prediction. J Mol Biol 322:891-901.
41. Telenti A, Zanger UM. 2008. Pharmacogenetics of anti-HIV drugs. Annu Rev Pharmacol Toxicol 48:227-256.
42. Thusberg J, Olatubosun A, Vihinen M. 2011. Performance of mutation pathogenicity prediction methods on missense variants. Hum Mutat 32:358-368.
43. Tishkoff SA, Reed FA, Friedlaender FR, Ehret C, Ranciaro A, Froment A, Hirbo JB, Awomoyi AA, Bodo J-M, Doumbo O, Ibrahim M, Juma AT, et al. 2009. The genetic structure and history of Africans and African Americans. Science 324:1035-1044.
44. Tsuchiya K, Gatanaga H, Tachikawa N, Teruya K, Kikuchi Y, Yoshino M, Kuwahara T, Shirasaka T, Kimura S, Oka S. 2004. Homozygous CYP2B6 *6 (Q172H and K262R) correlates with high plasma efavirenz concentrations in HIV-1 patients treated with standard efavirenz-containing regimens. Biochem Biophys Res Commun 319:1322-1326.
45. Turpeinen M, Raunio H, Pelkonen O. 2006. The functional role of CYP2B6 in human drug metabolism: substrates and inhibitors in vitro, in vivo and in silico. Curr Drug Metab 7:705-714.
46. Wang H, Tompkins LM. 2008. CYP2B6: new insights into a historically overlooked cytochrome P450 isozyme. Curr Drug Metab 9:598-610.
47. Wang L-L, Li Y, Zhou S-F. 2009. A bioinformatics approach for the phenotype prediction of nonsynonymous single nucleotide polymorphisms in human cytochromes P450. Drug Metab Dispos 37:977-991.
48. Ward BA, Gorski JC, Jones DR, Hall SD, Flockhart DA, Desta Z. 2003. The cytochrome P450 2B6 (CYP2B6) is the main catalyst of efavirenz primary and secondary metabolism: implication for HIV/AIDS therapy and utility of efavirenz as a substrate marker of CYP2B6 catalytic activity. J Pharmacol Exp Ther 306:287-300.
49. Watanabe T, Sakuyama K, Sasaki T, Ishii Y, Ishikawa M, Hirasawa N, Hiratsuka M. 2010. Functional characterization of 26 CYP2B6 allelic variants (CYP2B6.2-CYP2B6.28, except CYP2B6.22). Pharmacogenet Genomics 20:459-462.
50. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M. 2008. DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res 36:D901-D906.
51. Wyen C, Hendra H, Siccardi M, Platten M, Jaeger H, Harrer T, Esser S, Bogner JR, Brockmeyer NH, Bieniek B, Rockstroh J, Hoffmann C, et al. 2011. Cytochrome P450 2B6 (CYP2B6) and constitutive androstane receptor (CAR) polymorphisms are associated with early discontinuation of efavirenz-containing regimens. J Antimicrob Chemother 66:2092-2098.
52. Yue P, Li Z, Moult J. 2005. Loss of protein structure stability as a major causative factor in monogenic disease. J Mol Biol 353:459-473.
53. Zanger UM, Klein K, Saussele T, Blievernicht J, Hofmann MH, Schwab M. 2007. Polymorphic CYP2B6: molecular mechanisms and emerging clinical significance. Pharmacogenomics 8:743-759.
54. Zhao Y, Halpert JR. 2007. Structure-function analysis of cytochromes P450 2B. Biochim Biophys Acta 1770:402-412.
55. Zou M, Baitei EY, Alzahrani AS, Parhar RS, Al-Mohanna FA, Meyer BF, Shi Y. 2011. Mutation prediction by PolyPhen or functional assay, a detailed comparison of CYP27B1 missense mutations. Endocrine 40:14-20.
56. Zukunft J, Lang T, Richter T, Hirsch-Ernst KI, Nussler AK, Klein K, Schwab M, Eichelbaum M, Zanger UM. 2005. A natural CYP2B6 TATA box polymorphism (-82T-> C) leading to enhanced transcription and relocation of the transcriptional start site. Mol Pharmacol 67:1772-1782.