Three-dimensional quantitative structure activity relationship for Cyp2d6 substrates

Quantitative Structure-Activity Relationships

Volumn 21, Issue 4, 2002, Pages 357-368

  Snyder, Richard ^a   Sangar, Rajesh ^b   Wang, Jibo ^b   Ekins, Sean ^b,c  

^a BUTLER UNIVERSITY   (United States)

^b ELI LILLY AND COMPANY   (United States)

^c Lilly Corporate Center ^*  (United States)

Author keywords

[No Author keywords available]

Indexed keywords

COMPUTATIONAL CHEMISTRY; MAMMALS; MOLECULES; PATIENT MONITORING; PHARMACODYNAMICS; STRUCTURES (BUILT OBJECTS);

ACTIVE SITE; COMPUTATIONAL MOLECULAR MODELING; CRYSTALLIZED STRUCTURE; DRUG CANDIDATES; DRUG COMPANIES; HUMAN CYTOCHROMES P450; PHARMACOPHORES; THERAPEUTIC DRUG MONITORING; THREE DIMENSIONAL QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIP (3D QSAR); THREE-DIMENSIONAL QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP;

SUBSTRATES;

1,2,3,6 TETRAHYDRO 1 METHYL 4 PHENYLPYRIDINE; 7 ETHOXYCOUMARIN; AMIODARONE; AZELASTINE; CARTEOLOL; CHLORZOXAZONE; CINNARIZINE; CITALOPRAM; COUMARIN DERIVATIVE; CYTOCHROME P450; CYTOCHROME P450 2C5; CYTOCHROME P450 2D6; DEXFENFLURAMINE; DILTIAZEM; DOXEPIN; FLUNARIZINE; META TYRAMINE; MEXILETINE; N BUTYL 7 METHOXY 4 (AMINOMETHYL)COUMARIN; N ETHYL 7 METHOXY 4 (AMINOMETHYL)COUMARIN; NORTRIPTYLINE; PROMETHAZINE; SPARTEINE; THEOPHYLLINE; TYRAMINE; UNCLASSIFIED DRUG; VENLAFAXINE;

ARTICLE; CRYSTAL STRUCTURE; DRUG MONITORING; ENZYME ACTIVE SITE; ENZYME SPECIFICITY; ENZYME SUBSTRATE; MOLECULAR INTERACTION; MOLECULAR MODEL; PRIORITY JOURNAL; QUANTITATIVE STRUCTURE ACTIVITY RELATION;

EID: 0036794440     PISSN: 09318771     EISSN: None     Source Type: Journal    
DOI: 10.1002/1521-3838(200210)21:4<357::AID-QSAR357>3.0.CO;2-D     Document Type: Article

References (80)

1. Abdel-Rahman, S. M., Marcucci, K., Boge, T., Gotschall, R. R., Kearns, G. L., and Leeder, J. S., Potent inhibition of cytochrome P-450 2D6-mediated dextromethorphan O-demethylation by terbinafine, Drug Metab. Dispos. 27, 770-775 (1999).
2. Bertz, R. J., and Granneman, R. G., Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions, Clin. Pharmacokinet. 32, 210-258 (1997).
3. Bichara, N., Ching, M., Blake, C., Ghabrial, H., and Smallwood, R., Propranolol hydroxylation and N-desisopropylation by cytochrome P4502D6; studies using the yeast-expressed Enzyme and NADPH/O2 and cumene hydroperoxide-supported reactions, Drug Metab. Dispos. 24, 112-118 (1996).
4. Bravi G, and Wikel J. H., Application of MS-WHIM descriptors: 1. Introduction of new molecular surface properties and 2. Prediction of binding affinity data, Quant. Struct-Act. Relat. 19, 29-38 (2000)
5. Brosen, K., Drug-metabolizing enzymes and therapeutic drug monitoring in psychiatry, Ther. Drug Monitoring 18, 393-396 (1996).
6. Chen, H., Howald, W., and Juchau, M., Biosynthesis of all-trans-retinoic acid from all-trans-retinol: catalysis of all-transretinol oxidation by human P-450 cytochromes, Drug Metab. Dispos. 28, 315-322 (2000).
7. Coleman, T., Ellis, S. W., Martin, I. J., Lennard, M. S., and Tucker, G. T., 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is N-demethylated by cytochromes P450 2D6, 1A2, and 3A4 - implications for susceptibility to Parkinson's disease, J. Pharmacol. Exp. Ther. 277, 685-690 (1996).
8. Cosme, J., and Johnson, E. F., Engineering microsomal cytochrome P450 2C5 to be a soluble, monomeric enzyme. Mutations that alter aggregation, phospholipid dependence of catalysis, and membrane binding, J. Biol. Chem. 275, 2545-2553 (2000).
9. de Groot, M. J., Ackland, M. J., Horne, V. A., Alex, A. A., and Jones, B. C., A novel approach to predicting P450 mediated drug metabolism. CYP2D6 catalyzed N-dealkylation reactions and qualitative metabolite predictions using a combined protein and pharmacophore model for CYP2D6, J. Med. Chem. 42, 4062-4070 (1999).
10. de Groot, M. J., Ackland, M. J., Horne, V. A., Alex, A. A., and Jones, B. C., Novel approach to predicting P450-mediated drug metabolism: Development of a combined protein and pharmacophore model for CYP2D6, J. Med. Chem. 42, 1515-1524 (1999).
11. de Groot, M. J., Bijloo, G. J., Martens, B. J., van Acker, F. A. A., and Vermeulen, N. P. A., A refined substrate model for human cytochrome P450 2D6, Chem. Res. Toxicol. 10, 41-48 (1997).
12. de Groot, M. J., Bijloo, G. J., Van Acker, F. A. A., Fonseca Guerra, C., Snijders, J. G., and Vermeulen, N. P. E., Extension of a predictive substrate model for human cytochrome P4502D6, Xenobiotica 27, 357-368 (1997).
13. de Groot, M. J., Bijloo, G. J., Hansen, K. T., and Vermeulen, N. P. E., Computer prediction and experimental validation of cytochrome P450-2D6 dependent oxidation of GBR 12909 (1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine), Drug Metab. Dispos. 23, 667-669 (1995).
14. Dong, H., Heining, R. L., Thummel, K. E., Rettie, A. E., and Nelson, S. D., Involvement of human cytochrome P450 2D6 in the bioactivation of acetaminophen, Drug Metab. Dispos. 28, 1397-1400 (2000).
15. Ekins, S., Bravi, G., Binkley, S., Gillespie, J. S., Ring, B. J., Wikel, J. H., and Wrighton, S. A., Three and four dimensional-quantitative structure activity relationship (3D / 4D-QSAR) analyses of CYP2D6 inhibitors, Pharmacogenetics 9, 477-489 (1999).
16. Ekins, S., Bravi, G., Binkley, S., Gillespie, J. S., Ring, B. J., Wikel, J. H., and Wrighton, S. A., Three dimensional-quantitative structure activity relationship (3D-QSAR) analyses of inhibitors for CYP3A4, J. Pharmacol. Exp. Ther. 290, 429-438 (1999).
17. Ekins, S., Bravi, G., Binkley, S., Gillespie, J. S., Ring, B. J., Wikel, J. H., and Wrighton, S. A., Three and four dimensional-quantitative structure activity relationship (3D/4D-QSAR) analyses of CYP2C9 inhibitors, J. Pharmacol. Exp. Ther. 28, 994-1002 (2000).
18. Ekins, S., Bravi, G., Ring, B. J., Gillespie, T. A., Gillespie, J. S., Van den Branden, M., Wrighton, S. A., and Wikel, J. H., Three dimensional-quantitative structure activity relationship (3D-QSAR) analyses of substrates for CYP2B6, J. Pharmacol. Exp. Ther. 288, 21-29 (1999).
19. Ekins, S., Bravi, G., Wikel, J. H., and Wrighton, S. A., Three dimensional quantitative structure activity relationship (3D-QSAR) analysis of CYP3A4 substrates, J. Pharmacol. Exp. Ther. 291, 424-433 (1999).
20. Ekins, S., de Groot, M., and Jones, J. P., Pharmacophore and three dimensional quantitative structure activity relationship methods for modeling cytochrome P450 active sites, Drug Metab. Dispos. 29, 936-944 (2001).
21. Ekins, S., Ring, B. J., Bravi, G., Wikel, J. H., and Wrighton, S. A., Predicting drug-drug interactions in silico using pharmacophores: A paradigm for the next millenium, in: Guner, O. F. (Ed.), Pharmacophore, perception, development, and use in drug design, University International Line, San Diego 2000, pp. 269-299.
22. Ekins, S., Ring, B. J., Grace, J., McRobie-Belle, D. J., and Wrighton, S. A., Present and future in vitro approaches for drug metabolism, J. Pharm. Tox. Methods 44, 313-324 (2000).
23. Ekins, S., and Wrighton, S. A., Application of in silico approaches to predicting drug-drug interactions: A commentary, J. Pharm. Tox. Methods 44, 1-5 (2001).
24. Evert, B., Eichelbaum, M., Haubruck, H., and Zanger, U. M., Functional properties of CYP2D6 1 (wild-type) and CYP2D6 7 (His324Pro) expressed by recombinant baculovirus in insect cells, Naunyn-Schmiedeberg's Arch. Pharmacol. 355, 309-318 (1997).
25. Fukuda, T., Nishida, Y., Susumo, I., Hiroi, T., Naohara, M., Funae, Y., and Azuma, J., The decrease dc in Vivo clearance of CYP2D6 substrates by CYP2D6*10 might be caused not only by the low-expression but also by low affinity of CYP2D6, Arch. Biochem. Biophys. 380, 303-308 (2000).
26. Gasteiger J., Rudolph C., and Sadowski J., Automatic generation of 3D atomic coordinates for organic molecules, Tetrahedron Comput. Methodol. 3, 537-547 (1990).
27. Gilham, D. E., Cairns, W., Paine, M. J. I., Modi, S., Poulsom, R., Roberts, G. C. K., and Wolf, C. R., Metabolism of MPTP by cytochrome P4502D6 and the demonstration of 2D6 mRNA in human foetal and adult brain by in situ hybridization, Xenobiotica 27, 111-125 (1997).
28. Grace, J. M., Kinter, M. T., and Macdonald, T. L., Atypical metabolism of deprenyl and its enantiomer, (S)-(+)-N, a-dimethyl-N-propynylphenethylamine, by cytochrome P450 2D6, Chem. Res. Toxicol. 7, 286-290 (1994).
29. Haritos, V. S., Ghabrial, H., Ahokas, J. T., and Ching, M. S., Role of cytochrome P450 2D6 (CYP2D6) in the stereo-specific metabolism of E- and Z-doxepin, Pharmacogenetics 10, 591-603 (2000).
30. Hasemann, C. A., Ravichandran, J. A., Peterson., J. A., and Deisenhofer J., Crystal structure and refinement of cytochrome P450terp at 2.3 Å resolution, J. Mol. Biol. 236, 1169-1185 (1994).
31. Hiroi, T., Imaoa, S., and Funae, Y., Dopamine formation from tyramine by CYP2D6, Biochem. Biophys. Res. Comm. 249, 838-843 (1998).
32. Imai, T., Taketani, M., Suzu, T., Kusube, K., and Otagiri, M., In vitro identification of the human cytochrome P-450 enzymes involved in the N-demethylation of azelastine, Drug Metab, Dispos, 27, 942-946 (1999).
33. Jacobsen, W., Christians, U., and Benet, L. Z., In vitro evaluation of the disposition of a novel cysteine protease inhibitor, Drug Metab. Dispos. 28, 1343-1351 (2000).
34. Jones, B. C., Hyland, R., Ackland, M., Tyman, C. A., and Smith, D. A., Interaction of terfenadine and its primary metabolites with cytochrome P450 2D6, Drug Metab. Dispos. 26, 875-882 (1998).
35. Kariya, S., Isozaki, S., Uchino, K., Suzuki, T., and Narimatsu, S., Oxidative metabolism of flunarizine and cinnarizine by microsomes from B-lymphoblastoid cell lines expressing human cytochrome P450 enzymes, Biol. Pharm. Bull. 19, 1511-1514 (1996).
36. Koyama, E., Chiba, K., Tani, M., and Ishizaki, T., Reappraisal of human CYP isoforms involved in imipramine N-demethylation and 2-hydroxylation: a study using microsomes obtained from putative extensive and poor metabolizers of S-mephenytoin and eleven recombinant human CYPs, J. Pharmacol. Exp. Ther. 281, 1199-1210 (1997).
37. Koymans, L., Vermeulen, N. P. E., van Acker, S. A., te Koppele, J. M., Heykants, J. J. P., Lavrijsen, K., Meuldermans, W., and Donne-Op den Kelder, G. M., A predictive model for substrates of cytochrome P450-debrisoquine (2D6), Chem. Res. Toxicol. 5, 211-219 (1992).
38. Kudo, S., Uchida, M., and Odomi, M., Metabolism of carteolol by cDNA-expressed human cytochrome P450, Eur. J. Clin. Pharmacol. 52, 479-485 (1997).
39. Laskowski, R. A., Moss, D. S., and Thornton, J. M., Main-chain bond lengths and bond angles in protein structures, J. Mol. Biol. 231, 1049-1065 (1993).
40. Lessard, E., Fortin, A., Belanger, P. M., Beaune, P., Hamelin, B. A., and Turgeon, J., Role of CYP2D6 in the N-hydroxylation of procainamide, Pharmacogenetics 7, 381-390 (1997).
41. Lewis, D. F. V., Eddershaw, P. J., Goldfarb, P. S., and Tarbit, M. H., Molecular modelling of CYP2D6 based on an alignment with CYP102, Xenobiotica 27, 319-340 (1997).
42. Lightfoot, T. Ellis, S. W., Mahling, J., Ackland, M. J., Blaney, F. E., Bijloo, G. J., de Groot, M. J., Vermeulen, N. P. E., Blackburn, G. M., Lennard, M. S., and Tucker, G. T., Regioselective hydroxylation of debrisoquine by cytochrome P450 2D6: implications for active site modeling, Xenobiotica 30, 219-233 (2000).
43. Lin S. L., Nussinov R, Fischer D., and Wolfson H. J., Molecular Surface Representations by Sparse Critical Points, Proteins: Struct. Funct. and Genet. 18, 94-101 (1994).
44. Mankowski, D. C., Laddison, K. J., Christopherson, P. A., Ekins, S., Tweedie, D. J., and Lawton, M. P., Molecular cloning, expression, and characterization of CYP2D17 from cynomolgus monkey liver, Arch. Biochem. Biophys. 372, 189-196 (1999).
45. Margolis, J. M., O'Donnell, J. P., Mankowski, D. C., Ekins, S., and Obach, R. S., (R)-, (S)-, and racemic fluoxetine N-demethylation by human cytochrome P450 enzymes, Drug Metab. Dispos. 28, 1187-1191 (2000).
46. Mautz, D. S., Nelson, W. L., and Shen, D. D., and stereo-selective oxidation of metoprolol and bufuralol catalyzed by microsomes containing cDNA-expressed human P4502D6, Drug Metab. Dispos. 23, 513-517 (1995).
47. Meyer, U. A., Gut, J., Kronbach, T., Skoda, C., Meier, U. T., and Catin, T., The molecular mechanisms of two common polymorphisms of drug oxidation-evidence for functional changes in cytochrome P-450 isozymes catalysing bufuralol and mephenytoin oxidation, Xenobiotica 16, 449-464 (1986).
48. Molden, E., Asberg, A., and Christensen, H., CYP2D6 is involved in O-demethylation of diltiazem: an in vitro study with transfected human liver cells, Eur. J. Clin. Pharmacol. 56, 575-579 (2000).
49. Nakajima, M., Kobayashi, K., Shimada, N., Tokudome, S., Yamamoto, T., and Kuoiwa, Y., Involvement of CYP1A2 in mexiletine metabolism, Br. J. Clin. Pharmacol. 46, 55-62 (1998).
50. Nakajima, M., Nakamura, S., Tokudome, S., Shimada, N., Yamazaki, H., and Yokoi, T., Azelastine N-demethylation by cytochrome P-450 (CYP)3A4, CYP2D6, and CYP1A2 in human liver microsomes: evaluation of approach to predict contribution of multiple CYPs, Drug Metab. Dispos. 27, 1381-1391 (1999).
51. Nakamura, K., Yokoi, T., Inoue, K., Shimada, N., Ohaghi, N., Kume, T., and Kamataki, T., CYP2D6 is the principal cytochrome P450 responsible for metabolism of the histamine H1 antagonist promethazine in human liver microsomes, Pharmacogenetics 6, 449-457 (1996).
52. Obach, R. S., Metabolism of ezlopitant, a nonpeptidic substance P receptor antagonist, in liver microsomes: enzyme kinetics, cytochrome P450 isoform identity, and in vitro-in vivo correlation, Drug Metab. Dispos. 28, 1069-1076 (2000).
53. Ohyama, K., Nakajima, M., Nakamura, S., Shimada, N., Yamazaki, H., and 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. 28, 1303-1310 (2000).
54. Olesen, O. V., and Linnet, K., Hydroxylation and demethylation of the tricyclic antidepressant nortriptyline by cDNA-expressed human cytochrome P-450 isozymes, Drug Metab. Dispos. 25, 740-744 (1997).
55. Olesen, O. V., and Linnet, K., Identification of the human cytochrome P450 isoforms mediating in vitro N-dealkylation of perphenazine, Br. J. Clin. Pharmacol. 54, 563-571 (2000).
56. Ono, S., Tsutsui, M., Gonzalez, F. J., Satoh, T., Masubuchi, Y., Horie, T., Suzuki, T., and Narimatsu, S., Oxidative metabolism of bunitrolol by complementary DNA-expressed human cytochrome P450 isozymes in a human hepatoma cell line (Hep G2) using recombinant vaccinia virus, Pharmacogenetics 5, 97-102 (1995).
57. Patten, C. J., Smith, T. J., Murphy, S. E., Wang, M.-H., Lee, J., Tynes, R. E., Koch, P., and Yang, C. S., Kinetic analysis of the activation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone by heterologously expressed human P450 enzymes and the effect of P450-specific chemical inhibitors on this activation in human liver microsomes, Arch. Biochem. Biophys. 333, 127-138 (1996).
58. Poulos, T. L., Finzel, B. C., and Howard, A. J., Crystal structure of substrate-free Pseudomonas putida cytochrome P-450, Biochemistry (Mosc) 25, 5314-5322 (1986).
59. Ring, B. J., Eckstein, J. A., Gillespie, J. S., Binkley, S. N., Van den Branden, M., and Wrighton, S. A., Identification of the human cytochromes P450 responsible for in vitro formation of the R- and S-Norfluoxetine, J. Pharmacol. Exp. Ther. 297, 1044-1050 (2001).
60. Rochat, B., Amey, M., Gillet, M., Meyer, U. A., and Baumann, P., Identification of three cytochrome P450 isozymes involved in N-demethylation of citalopram enantiomers in human liver microsomes, Pharmacogenetics 7, 1-10 (1997).
61. Sali, A., and Blundell, T. L., Comparative protein modelling by satisfaction of spatial restraints, J. Mol. Biol 234, 779-815 (1993).
62. Shimada, T., Tsumura, F., and Yamazaki, H., Prediction of human liver microsomal oxidations of 7-ethoxycoumarin and chlorzoxazone with kinetic parameters of recombinant cytochrome P-450 enzymes, Drug Metab. Dispos. 27, 1274-1280 (1999).
63. Shimada, T., Yamazaki, H., Mimura, M., Inui, Y., and Guengerich, F. P., Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians, J. Pharmacol. Exp. Ther. 270, 414-423 (1994).
64. Stormer, E., von Moltke, L. L., Shader, R. I., and Greenblatt, D. J., Metabolism of the antidepressant mirtazapine in vitro: contribution of cytochromes P-450 1A2, 2D6, and 3A4, Drug Metab. Dispos. 28, 1168-1175 (2000).
65. Su, P., Couttis, R. T., Baker, G. B., and Daneshtalab, M., Analysis of imipramine and three metabolites produced by isozyme CYP2D6 expressed in a human cell line, Xenobiotica 23, 1289-1298 (1993).
66. Sevrioukova, I. F., Li, H., Zhang, J. A., Peterson, J. A., and Poulos, T. L., Structure of cytochrome P450-redox partner electron-transfer complex, Proc. Natl. Acad. Sci. USA 96, 1863-1868 (1999).
67. Szklarz, G. D., Graham, S. E., and Paulsen, M. D., Molecular modeling of mammalian cytochromes P450: application to study enzyme function, Vita. Horm. 58, 53-87 (2000).
68. Thompson, J. D., Higgins, D. G., and Gibson, T. J., CLUS-TALW: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice, Nucleic Acids Res. 22, 4673-4680 (1994).
69. Todeschini R., Lasagni M., and Marengo E., New molecular descriptors for 2D and 3D structures. Theory, J. Chemometrics 8, 263-272 (1994).
70. Todeschini R., and Gramatica P., 3D-modelling and prediction by WHIM descriptors. Part 5. Theory Development and Chemical Meaning of WHIM Descriptors, Quant. Struct.-Act. Relat. 16, 113-119 (1997).
71. Tucker, G. T., Lennard, M. S., Ellis, S. W., Woods, H. F., Cho, A. K., Lin, L. Y., Hiratsuka, A., Schmitz, D. A., and Chu, T. Y. Y., The demethylenation of methylenedioxymethamphetamine ("ecstasy") by debsoquine hydroxylase (CYP2D6), Biochem. Pharmacol. 47, 1151-1156 (1994).
72. Venhorst, J., Onderwater, R. C. A., Meerman, J. H. N., Comandeur, J. N. M., and Vermeulen, N. P. E., Influence of N-substitution of 7-methoxy-4-(aminomethyl)-coumarin on cytochrome P450 metabolism and selectivity, Drug Metab. Dispos. 28, 1524-1532 (2000).
73. Venkatakrishnan, K., von Moltke, L. L., and Greenblatt, D. J., Nortriptyline E-10-hydroxylation in vitro is mediated by human CYP2D6 (high affinity) and CYP3A4 (low affinity): implications for interactions with enzyme-inducing drugs, J. Clin. Pharmacol. 39, 567-577 (1999).
74. Von Moltke, L. L., Greenblatt, D. J., Grassi, J. M., Granda, B. W., Venkatakrishnan, K., Schmider, J., Harmatz, J. S., and Shader, R. I., Multiple human cytochromes contribute to biotransformation of dextromethorphan In vitro; role of CYP2C9, CYP2C19, CYP2D6, and CYP3A, J. Pharm. Pharmacol. 50, 997-1004 (1998).
75. Voorman, R. L., Maio, S. M., Hauer, M. J., Sanders, P. E., Payne, N. A., and Ackland, M. J., Metabolism of delavirdine, a human immunodeficiency virus type-1 reverse transcriptase inhibitor, by microsomal cytochrome P450 in humans, rats, and other species: probable involvement of CYP2D6 and CYP3A4, Drug Metab. Dispos. 26, 631-639 (1998).
76. Williams, P. A., Cosme, J., Sridhar, V., Johnson, E. F., and McRee, D. E., Mammalian microsomal cytochrome P450 monooxygenase: structural adaptations for membrane binding and functional diversity, Mol. Cell 5, 121-131 (2000).
77. Wolff, T., Distelrath, L. M., Worthington, M. T., Groopman, J. D., Hammons, G. J., Kadlubar, F. F., Prough, R. A., Martin, M. V., and Guengerich, F. P., Substrate specificty of human liver cytochrome P-450 debrisoquine 4-hydroxylase probed using immunochmical inhibition and chemical modeling, Cancer Res. 45, 2116-2122 (1985).
78. Wrighton, S.A., Vandenbranden, M., Stevens, J. C., and Shipley, L. A., In vitro methods for assessing human hepatic drug metabolism: their use in drug development, Drug Metab. Rev. 25, 453-84 (1993).
79. Yoshii, K., Kobayashi, K., Tsumuji, M., Tani, M., Shimada, N., and Chiba, K., Identification of human cytochrome P450 isoforms involved in the 7-hydroxylation of chlorpromazine by human liver microsomes, Life Sci. 67, 175-184 (2000).
80. Zhang, Z., and Kaminsky, L., Characterization of human cytochromes P-450 involved in theophylline 8-hydroxylation, Biochem. Pharmacol. 50, 205-211 (1995).