A pragmatic approach using first-principle methods to address site of metabolism with implications for reactive metabolite formation

Journal of Chemical Information and Modeling

Volumn 52, Issue 3, 2012, Pages 686-695

  Hsiao, Ya Wen ^a   Petersson, Carl ^a   Svensson, Mats A ^a   Norinder, Ulf ^a,b  

^a ASTRAZENECA R AND D   (Sweden)

^b UPPSALA UNIVERSITY   (Sweden)

Author keywords

[No Author keywords available]

Indexed keywords

AROMATIC COMPOUNDS; BIOCHEMISTRY; BIOMOLECULES; DENSITY FUNCTIONAL THEORY; DESIGN FOR TESTABILITY; FORECASTING; HYDROXYLATION; METABOLISM; METABOLITES;

AROMATIC HYDROXYLATION; AROMATIC SUBSTRATES; FIRST PRINCIPLE METHOD; FIRST-PRINCIPLE DENSITY-FUNCTIONAL THEORIES; INTRINSIC REACTIVITY; REACTIVE METABOLITES; RELATIVE STABILITIES; XENOBIOTIC METABOLISM;

SUBSTRATES;

CYTOCHROME P450; EPOXIDE; LIGAND; XENOBIOTIC AGENT;

ARTICLE; BINDING SITE; CHEMICAL STRUCTURE; CHEMISTRY; CONFORMATION; ELECTRON; HYDROXYLATION; METABOLISM; QUANTUM THEORY; THERMODYNAMICS;

BINDING SITES; CYTOCHROME P-450 ENZYME SYSTEM; ELECTRONS; EPOXY COMPOUNDS; HYDROXYLATION; LIGANDS; MODELS, MOLECULAR; MOLECULAR CONFORMATION; QUANTUM THEORY; THERMODYNAMICS; XENOBIOTICS;

EID: 84859208478     PISSN: 15499596     EISSN: 1549960X     Source Type: Journal    
DOI: 10.1021/ci200523f     Document Type: Article

References (86)

1. Thompson, R. A.; Isin, E. M.; Li, Y.; Weaver, R.; Weidolf, L.; Wilson, I.; Claesson, A.; Page, K.; Dolgos, H.; Kenna, J. G. Risk Assessment and Mitigation Strategies for Reactive Metabolites in Drug Discovery and Development Chem.-Biol. Interact. 2011, 192, 65-71
2. Prakash, C.; Sharma, R.; Gleave, M.; Nedderman, A. In Vitro Screening Techniques for Reactive Metabolites for Minimizing Bioactivation Potential in Drug Discovery Curr. Drug. Metab. 2008, 9, 952-964
3. Walsh, J. S.; Miwa, G. T. Bioactivation of Drugs: Risk and Drug Design Annu. Rev. Pharmacol. Toxicol. 2011, 51, 145-167
4. Korzekwa, K. R.; Swinney, D. C.; Trager, W. F. Isotopically Labeled Chlorobenzenes as Probes for the Mechanism of Cytochrome P-450 Catalyzed Aromatic Hydroxylation Biochemistry 1989, 28, 9019-9027
5. Jones, J. P.; Mysinger, M.; Korzekwa, K. R. Computational Models for Cytochrome P450: A Predictive Electronic Model for Aromatic Oxidation and Hydrogen Atom Abstraction Drug Metab. Dispos. 2002, 30, 7-12
6. Bathelt, C. M.; Ridder, L.; Mulholland, A. J.; Harvey, J. N. Mechanism and Structure-Reactivity Relationships for Aromatic Hydroxylation by Cytochrome P450 Org. Biomol. Chem. 2004, 2, 2998-3005
7. Tarcsay, á.; Keserü, G. M. In Silico Site of Metabolism Prediction of Cytochrome P450-Mediated Biotransformations Expert. Opin. Metab. Toxicol. 2011, 7, 299-312
8. Leffler, J. E. Parameters for the Description of Transition States Science 1953, 117, 340-341
9. Hammond, G. S. A Correlation of Reaction Rates J. Am. Chem. Soc. 1955, 77, 334-338
10. Rydberg, P.; Vasanthanathan, P.; Oostenbrink, C.; Olsen, L. Fast Prediction of Cytochrome P450 Mediated Drug Metabolism Chem. Med. Chem. 2009, 4, 2070-2079
11. Lee, B.; Richards, F. M. The Interpretation of Protein Structures: Estimation of Static Accessibility J. Mol. Biol. 1971, 55, 379-400
12. The CCP4 Suite: Programs for Protein Crystallography. Acta Cryst. D 1994, 50, 760-763, Collaborative Computational Project, Number 4, 1994.
13. Ogliaro, F.; Filatov, M.; Shaik, S. Alkane Hydroxylation by Cytochrome P450: Is Kinetic Isotope Effect a Reliable Probe of Transition State Structure? Eur. J. Inorg. Chem. 2000, 12, 2455-2458
14. Olsen, L.; Rydberg, P.; Rod, T. H.; Ryde, U. Prediction of Activation Energies for Hydrogen Abstraction by Cytochrome P450 J. Med. Chem. 2006, 49, 6489-6499
15. Rydberg, P.; Ryde, U.; Olsen, L. Prediction of Activation Energies for Aromatic Oxidation by Cytochrome P450 J. Phys. Chem. A 2008, 112, 13058-13065
16. Frisch, J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, revision A.1; Gaussian Inc.: Wallingford, CT, 2009.
17. Becke, A. D. Density-Functional Thermochemistry. III. The Role of Exact Exchange J. Chem. Phys. 1993, 98, 5648-5652
18. Lee, C.; Yang, W.; Parr, R. G. Development of the Colle-Salvetti Correlation-Energy Formula into a Functional of the Electron Density Phys. Rev. B 1988, 37, 785-789
19. Hehre, W. J.; Ditchfield, R.; Pople, J. A. Self-Consistent Molecular Orbital Methods. 12. Further Extensions of Gaussian-Type Basis Sets for Use in Molecular-Orbital Studies of Organic-Molecules J. Chem. Phys. 1972, 56, 2257-2261
20. Hariharan, P. C.; Pople, J. A. Influence of Polarization Functions on Molecular-Orbital Hydrogenation Energies Theor. Chem. Acc. 1973, 28, 213-222
21. Francl, M. M.; Pietro, W. J.; Hehre, W. J.; Binkley, J. S.; Defrees, D. J.; Pople, J. A.; Gordon, M. S. Self-Consistent Molecular Orbital Methods. 23. A Polarization-Type Basis Set for 2nd-Row Elements J. Chem. Phys. 1982, 77, 3654-3665
22. Tomasi, J.; Mennucci, B.; Cammi, R. Quantum Mechanical Continuum Solvation Models Chem. Rev. 2005, 105, 2999-3093
23. Bathelt, C. M.; Mulholland, A. J.; Harvey, J. N. QM/MM Modeling of Benzene Hydroxylation in Human Cytochrome P450 2C9 J. Phys. Chem. A 2008, 112, 13149-13156
24. Denisov, I.; Makris, T.; Sligar, S.; Schlichting, I. Structure and Chemistry of Cytochrome P450 Chem. Rev. 2005, 105, 2253-2278
25. Guroff, G.; Daly, J. W.; Jerina, D. M.; Renson, J.; Witkop, B.; Undenfriend, S. Hydroxylation-Induced Migration: The NIH Shift Science 1967, 157, 1524-1530
26. Jerina, D. M.; Daly, J. W.; Witkop, B.; Zaltzman-Nirenberg, P.; Undenfriend, S. The Role of Arene Oxide-oxepin Systems in the Metabolism of Aromatic Substrates. III. Formation of 1,2-Naphthalene Oxide from Naphthalene by Liver Microsomes J. Am. Chem. Soc. 1968, 90, 6525-6527
27. Bu, H.; Kang, P.; Deese, A.; Zhao, P.; Pool, W. Human in Vitro Glutathionyl and Protein Adducts of Carbamazepine-10,11-Epoxide, a Stable and Pharmacologically Active Metabolite of Carbamazepine Drug Metab. Dispos. 2005, 33, 1920-1924
28. Chen, Q.; Doss, G.; Tung, E.; Liu, W.; Tang, Y.; Braun, M.; Didolkar, V.; Strauss, J.; Wang, R.; Stearns, R.; Evans, D.; Baillie, T.; Tang, W. Evidence for the Bioactivation of Zomepirac and Tolmetin by an Oxidative Pathway: Identification of Glutathione Adducts in Vitro in Human Liver Microsomes and in Vivo in Rats Drug Metab. Dispos. 2006, 34, 145-151
29. Zheng, J.; Hanzlik, R. Premercapturic Acid Metabolites of Bromobenzene Derived via Its 2,3-Oxide and 3,4-Oxide Metabolites Xenobiotica 1991, 21, 535-546
30. Koch, P.; Hirst, D.; von Wartburg, B. Biological Fate of Sirdalud in Animals and Man Xenobiotica 1989, 19, 1255-1265
31. Mutlib, A.; Dickenson, P.; Chen, S.; Espina, R.; Daniels, J.; Gan, L. Bioactivation of Benzylamine to Reactive Intermediates in Rodents: Formation of Glutathione, Glutamate, and Peptide Conjugates Chem. Res. Toxicol. 2002, 15, 1190-1207
32. Watt, K.; Morin, D.; Kurth, M.; Mercer, R.; Plopper, C.; Buckpitt, A. Glutathione Conjugation of Electrophilic Metabolites of 1-Nitronaphthalene in Rat Tracheobronchial Airways and Liver: Identification by Mass Spectrometry and Proton Nuclear Magnetic Resonance Spectroscopy Chem. Res. Toxicol. 1999, 12, 831-839
33. Dansette, P. M.; Bertho, G.; Mansuy, D. First Evidence that Cytochrome P450 May Catalyze both S-Oxidation and Epoxidation of Thiophene Derivatives Biochem. Biophys. Res. Commun. 2005, 338, 450-455
34. Mannens, G. S. J.; Hendrickx, J.; Janssen, C. G. M.; Chien, S.; Van Hoof, B.; Verhaeghe, T.; Kao, M.; Kelley, M. F.; Goris, I.; Bockx, M.; Verreet, B.; Bialer, M.; Meuldermans, W. The Absorption, Metabolism, and Excretion of the Novel Neuromodulator RWJ-333369 (1,2-Ethanediol, [1-2-Chlorophenyl]-, 2-Carbamate, [S]-) in Humans Drug Metab. Dispos. 2007, 35, 554-565
35. Mamidi, R. N. V. S.; Mannens, G.; Annaert, P.; Hendrickx, J.; Goris, I.; Bockx, M.; Janssen, C. G. M.; Kao, M.; Kelley, M. F.; Meuldermans, W. Metabolism and Excretion of RWJ-333369 [1,2-Ethanediol, 1-(2-Chlorophenyl)-, 2-Carbamate, (S)-] in Mice, Rats, Rabbits, and Dogs Drug Metab. Dispos. 2007, 35, 566-575
36. Wong, S. G.; Fan, P. W.; Subramanian, R.; Tonn, G. R.; Henne, K. R.; Johnson, M. G.; Lohr, M. T.; Wong, B. K. Bioactivation of a Novel 2-Methylindole-Containing Dual Chemoattractant Receptor-Homologous Molecule Expressed on T-Helper Type-2 Cells/D-Prostanoid Receptor Antagonist Leads to Mechanism-Based CYP3A Inactivation: Glutathione Adduct Characterization and Prediction of In Vivo Drug-Drug Interaction Drug Metab. Dispos. 2010, 38, 841-850
37. Singh, R.; Elipe, M. V. S.; Pearson, P. G.; Arison, B. H.; Wong, B. K.; White, R.; Yu, X.; Burgey, C. S.; Lin, J. H.; Baillie, T. A. Metabolic Activation of a Pyrazinone-Containing Thrombin Inhibitor. Evidence for Novel Biotransformation Involving Pyrazinone Ring Oxidation, Rearrangement, and Covalent Binding to Proteins Chem. Res. Toxicol. 2003, 16, 198-207
38. Yergey, J. A.; Trimble, L. A.; Silva, J.; Chauret, N.; Li, C.; Therien, M.; Grimm, E.; Nicoll-Griffith, D. A. In Vitro Metabolism of the COX-2 Inhibitor DFU, Including a Novel Glutathione Adduct Rearomatizationa Drug Metab. Dispos. 2001, 29, 638-644
39. Chen, H.; Grover, S.; Yu, L.; Walker, G.; Mutlib, A. Bioactivation of Lamotrigine in Vivo in Rat and in Vitro in Human Liver Microsomes, Hepatocytes, and Epidermal Keratinocytes: Characterization of Thioether Conjugates by Liquid Chromatography/Mass Spectrometry and High Field Nuclear Magnetic Resonance Spectroscopy Chem. Res. Toxicol. 2010, 23, 159-170
40. SahaliSahly, Y.; Balani, S. K.; Lin, J. H.; Baillie, T. A. In Vitro Studies on the Metabolic Activation of the Furanopyridine L-754,394, a Highly Potent and Selective Mechanism-Based Inhibitor of Cytochrome P450 3A4 Chem. Res. Toxicol. 1996, 9, 1007-1012
41. Williams, D. P.; Antoine, D. J.; Butler, P. J.; Jones, R.; Randle, L.; Payne, A.; Howard, M.; Gardner, I.; Blagg, J.; Park, B. K. The Metabolism and Toxicity of Furosemide in the Wistar Rat and CD-1 Mouse: a Chemical and Biochemical Definition of the Toxicophore J. Pharmacol. Exp. Ther. 2007, 322, 1208-1220
42. Born, S. L.; Rodriguez, P. A.; Eddy, C. L.; LehmanMcKeeman, L. D. Synthesis and Reactivity of Coumarin 3,4-Epoxide Drug Metab. Dispos. 1997, 25, 1318-1323
43. Born, S. L.; Caudill, D.; Fliter, K. L.; Purdon, M. P. Identification of the Cytochromes P450 that Catalyze Coumarin 3,4-Epoxidation and 3-Hydroxylation Drug Metab. Dispos. 2002, 30, 483-487
44. Reddy, V.; Doss, G.; Creighton, M.; Kochansky, C.; Vincent, S.; Franklin, R.; Karanam, B. Identification and Metabolism of a Novel Dihydrohydroxy-S- glutathionyl Conjugate of a Peroxisome Proliferator-activated Receptor Agonist, MK-0767 [(±)-5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[(4-tr ifluoromethyl)phenyl]methyl] enzamide], in Rats Drug Metab. Dispos. 2004, 32, 1154-1161
45. Zhuo, X.; Hartz, R. A.; Bronson, J. J.; Wong, H.; Ahuja, V. T.; Vrudhula, V. M.; Leet, J. E.; Huang, S.; Macor, J. E.; Shu, Y.-Z. Comparative Biotransformation of Pyrazinone-Containing Corticotropin-Releasing Factor Receptor-1 Antagonists: Minimizing the Reactive Metabolite Formation Drug Metab. Dispos. 2010, 38, 5-15
46. Mutlib, A. E.; Shockcor, J.; Chen, S. Y.; Espina, R. J.; Pinto, D. J.; Orwat, M. J.; Prakash, S. R.; Gant, L. S. Disposition of 1-[3-(Aminomethyl) phenyl]-N-[3-fluoro-2′(methylsulfonyl)-[1,1″- biphenyl]-4-yl]-3- (trifluoromethyl)-1H-Pyrazole-5-Carboxamide (DPC 423) by Novel Metabolic Pathways. Characterization of Unusual Metabolites by liquid Chromatography/Mass Spectrometry and NMR Chem. Res. Toxicol. 2002, 15, 48-62
47. Kitani, M.; Miyamoto, G.; Nagasawa, M.; Yamada, T.; Matsubara, J.; Uchida, M.; Odomi, M. Biotransformation of the Novel Inotropic Agent Toborinone (OPC-18790) in Rats and Dogs-Evidence for the Formation of Novel Glutathione and Two Cysteine Conjugates Drug Metab. Dispos. 1997, 25, 663-674
48. Koenigs, L. L.; Trager, W. F. Mechanism-Based Inactivation of Cytochrome P450 2B1 by 8-Methoxypsoralen and Several Other Furanocoumarins Biochemistry 1998, 37, 13184-13193
49. McCormick, A. M.; Napoli, J. L.; Schnoes, H. K.; Deluca, H. F. Isolation and Identification of 5,6-Epoxyretinoic Acid-Biologically-Active Metabolite of Retinoic Acid Biochemistry 1978, 17, 4085-4090
50. Chen, H.; Shockcor, J.; Chen, W.; Espina, R.; Gan, L.-S.; Mutlib, A. E. Delineating Novel Metabolic Pathways of DPC 963, a Non-Nucleoside Reverse Transcriptase Inhibitor, in Rats. Characterization of Glutathione Conjugates of Postulated Oxirene and Benzoquinone Imine Intermediates by LC/MS and LC/NMR Chem. Res. Toxicol. 2002, 15, 388-399
51. Mutlib, A.; Chen, H.; Shockcor, J.; Espina, R.; Chen, S.; Cao, K.; Du, A.; Nemeth, G.; Prakash, S.; Gan, L.-S. Characterization of Novel Glutathione Adducts of a Non-Nucleoside Reverse Transcriptase Inhibitor, (S)-6-Chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-3,4-dihydro-2(1H) -quinazolinone (DPC 961), in Rats. Possible Formation of an Oxirene Metabolic Intermediate from a Disubstituted Alkyne Chem. Res. Toxicol. 2000, 13, 775-784
52. Machinist, J. M.; Mayer, M. D.; Shet, M. S.; Ferrero, J. L.; Rodrigues, A. D. Identification of the Human Liver Cytochrome-P450 Enzymes Involved in the Metabolism of Zileuton (ABT-077) and ITS N-Dehydroxylated Metabolite, ABBOTT-66193 Drug Metab. Dispos. 1995, 23, 1163-1174
53. Turgeon, J.; Fiset, C.; Giguere, R.; Gilbert, M.; Moerike, K.; Rouleau, J. R.; Kroemer, H. K.; Eichelbaum, M.; Grechbelanger, O.; Belanger, P. M. Influence of Debrisoquine Phenotype and of Quinidine on Mexiletine Disposition in Man J. Pharmacol. Exp. Ther. 1991, 259, 789-798
54. Nakajima, M.; Kobayashi, K.; Shimada, N.; Tokudome, S.; Yamamoto, T.; Kuroiwa, Y. Involvement of CYPIA2 in Mexiletine Metabolism Br. J. Clin. Pharmacol. 1998, 46, 55-62
55. Imaoka, S.; Enomoto, K.; ODA, Y.; Asada, A.; Fujimori, M.; Shimada, T.; Fujita, S.; Guengerich, F. P.; Funae, Y. Lidocaine Metabolism by Human Cytochrome-P-450s Pirified from Hepatic Microsomes-Comparison of Those with Rar Hepatic Cytochrome-P-450s J. Pharmacol. Exp. Ther. 1990, 255, 1385-1391
56. Matzke, G.; Frye, R.; Early, J.; Straka, R.; Carson, S. Evaluation of the Influence of Diabetes Mellitus on Antipyrine Metabolism and CYP1A2 and CYP2D6 Activity Pharmacotherapy 2000, 20, 182-190
57. Engel, G.; Hofmann, U.; Heidemann, H.; Cosme, J.; Eichelbaum, M. Antipyrine as a Probe for Human Oxidative Drug Metabolism: Identification of the Cytochrome P450 Enzymes Catalyzing 4-Hydroxyantipyrine, 3- Hydromethylantipyrine, and Norantipyrine Formation Clin. Pharmacol. Ther. 1996, 59, 613-623
58. Coulet, M.; Dacasto, M.; Eeckhoutte, C.; Larrieu, G.; Sutra, J.; Alvinerie, M.; Mace, K.; Pfeifer, A.; Galtier, P. Identification of Human and Rabbit Cytochromes P450 1A2 as Major Isoforms Involved in Thiabendazole 5-Hydroxylation Fundam. Clin. Pharmacol. 1998, 12, 225-235
59. Koyama, E.; Chiba, K.; Tani, M.; 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. 1997, 281, 1199-1210
60. Ching, M. S.; Bichara, N.; Blake, C. L.; Ghabrial, H.; Tukey, R. H.; Smallwood, R. A. Propranolol 4- and 5-Hydroxylation and N-Desisopropylation by Cloned Human Cytochrome P4501A1 and P4501A2 Drug Metab. Dispos. 1996, 24, 692-694
61. Masubuchi, Y.; Hosokawa, S.; Horie, T.; Suzuki, T.; Ohmori, S.; Kitada, M.; Narimatsu, S. Cytochrome-P450 Isozymes Involved in Propranolol Metabolism in Human Liver-Microsomes-The Role of CYP2D6 as Ring-Hydroxylase and CYP1A2 as N-Desisopropylase Drug Metab. Dispos. 1994, 22, 909-915
62. Kariya, S.; Isozaki, S.; Uchino, K.; Suzuki, T.; Narimatsu, S. Oxidative Metabolism of Flunarizine and Cinnarizine by Microsomes from B-Lymphoblastoid Cell Lines Expressing Human Cytochrome P450 Enzymes Biol. Pharmacol. Bull. 1996, 19, 1511-1514
63. Thijssen, H.; Flinois, J.; Beaune, P. Cytochrome P4502C9 is the Principal Catalyst of Racemic Acenocoumarol Hydroxylation Reactions in Human Liver Microsomes Drug Metab. Dispos. 2000, 28, 1284-1290
64. Ma, X. C.; Idle, J. R.; Krausz, K. W.; Gonzalez, F. Metabolism of Melatonin by Human Cytochromes P450 Drug Metab. Dispos. 2005, 33, 489-494
65. Shimada, T.; Tsumura, F.; 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. 1999, 27, 1274-1280
66. Guitton, J.; Buronfosse, T.; Desage, M.; Flinois, J. P.; Perdrix, J. P.; Brazier, J. L.; Beaune, P. Possible Involvement of Multiple Human Cytochrome P450 Isoforms in the Liver Metabolism of Propofol Brit. J. Anaesth. 1998, 80, 788-795
67. Ozawa, S.; Ohta, K.; Miyajima, A.; Kurebayashi, H.; Sunouchi, M.; Shimizu, M.; Murayama, N.; Matsumoto, Y.; Fukuoka, M.; Ohno, Y. Metabolic Activation of O-Phenylphenol to a Major Cytotoxic Metabolite, Phenylhydroquinone: Role of Human CYP1A2 and Rat CYP2C11/CYP2E1 Xenobiotica 2000, 30, 1005-1017
68. Otake, Y.; Walle, T. Oxidation of the Flavonoids Galangin and Kaempferide by Human Liver Microsomes and CYP1A1, CYP1A2, and CYP2C9 Drug Metab. Dispos. 2002, 30, 103-105
69. Coller, J. K.; Somogyi, A. A.; Bochner, F. Comparison of (S)-Mephenytoin and Proguanil Oxidation in Vitro: Contribution of Several CYP Isoforms Br. J. Clin. Pharmacol. 1999, 48, 158-167
70. Rettie, A. E.; Korzekwa, K. R.; Kunze, K. L.; Lawrence, R. F.; Eddy, A. C.; Aoyama, T.; Gelboin, H. V.; Gonzalez, F. J.; Trager, W. F. Hydroxylation of Warfarin by Human cDNA-Expressed Cytochrome-P-450-A Role for P-4502C9 in the Etiology of (S)-Warfarin DRUG-Interactions Chem. Res. Toxicol. 1992, 5, 54
71. Zhang, Z.; Fasco, M.; Huang, Z.; Guengerich, F.; Kaminsky, L. Human Cytochromes P4501A1 and P4501A2: R-Warfarin Metabolism as a Probe Drug Metab. Dispos. 1995, 23, 1339-1345
72. Ekström, G.; Gunnarsson, U. Ropivacaine, a New Amide-Type Local Anesthetic Agent, is Metabolized by Cytochromes P450 1A and 3A in Human Liver Microsomes Drug Metab. Dispos. 1996, 24, 955-961
73. Bloomer, J.; Clarke, S.; Chenery, R. In Vitro Identification of the P450 Enzymes Responsible for the Metabolism of Ropinirole Drug Metab. Dispos. 1997, 25, 840-844
74. Tracy, T. S.; Rosenbluth, B. W.; Wrighton, S. A.; Gonzalez, F. J.; Korzekwa, K. R. Role of Cytochrome-P450 2C9 and an Allelic Variant in the 4′-Hydroxylation of (R)-Flurbiprofen and (S)-Flurbiprofen Biochem. Pharmacol. 1995, 49, 1269-1275
75. Liu, G.; Gelboin, H. V.; Myers, M. J. Role of Cytochrome P450 IA2 in Acetanilide 4-Hydroxylation as Determined with cDNA Expression and Monoclonal Antibodies Arch. Biochem. Biophys. 1991, 284 (2) 400-406
76. Yamazaki, H.; Guo, Z.; Persmark, M.; Mimura, M.; Inoue, K.; Guengerich, F.; Shimada, T. Bufuralol Hydroxylation by Cytochrome-P450 2D6 AND 1A2 Enzymes in Human Liver-Microsomes Mol. Pharmacol. 1994, 46, 568-577
77. Yamazaki, H.; Inoue, K.; Shaw, P.; Checovich, W. J.; Guengerich, F.; Shimada, T. Different Contributions of Cytochrome P450 2C19 and 3A4 in the Oxidation of Omeprazole by Human Liver Microsomes: Effects of Contents of These Two Forms in Individual Human Samples J. Pharmacol. Exp. Ther. 1997, 283, 434-442
78. Oldham, H. G.; Clarke, S. E. In Vitro Identification of the Human Cytochrome P450 Enzymes Involved in the Metabolism of R(+)- and S(-)-Carvedilol Drug Metab. Dispos. 1997, 25, 970-977
79. Kim, K.; Isin, E.; Yun, C.; Kim, D.; Guengerich, F. Kinetic Deuterium Isotope Effects for 7-Alkoxycoumarin O-Dealkylation Reactions Catalyzed by Human Cytochromes P450 and in Liver Microsomes-Rate-Limiting C-H Bond Breaking in Cytochrome P450 1A2 Substrate Oxidation FEBS J. 2006, 273, 2223-2231
80. Spaldin, V.; Madden, S.; Adams, D. A.; Edwards, R. J.; Davies, D. S.; Park, B. K. Determination of Human Hepatic Cytochrome P4501A2 Activity in-Vitro-Use of Tacrine as an Isoenzyme-Specific Probe Drug Metab. Dispos. 1995, 23, 929-934
81. Ward, B. A.; Morocho, A.; Kandil, A.; Galinsky, R. E.; Flockhart, D. A.; Desta, Z. Characterization of Human Cytochrome P450 Enzymes Catalyzing Domperidone N-Dealkylation and Hydroxylation in Vitro Br. J. Clin. Pharmacol. 2004, 58, 277-287
82. He, X.; Tang, L.; Wang, S.; Cai, Q.; Wang, J.; Hong, J. Efficient Activation of Aflatoxin B-1 by Cytochrome P450 2A13, an Enzyme Predominantly Expressed in Human Respiratory Tract Int. J. Cancer 2006, 118, 2665-2671
83. Mancy, A.; Antignac, M.; Minoletti, C.; Dijols, S.; Mouries, V.; Duong, N. T. H.; Battioni, P.; Dansette, P. M.; Mansuy, D. Diclofenac and its Derivatives as Tools for Studying Human Cytochromes P450 Active Sites: Particular Efficiency and Regioselectivity of P4502Cs Biochemistry 1999, 38, 14264-14270
84. Bort, R.; Mace, K.; Boobis, A.; Gomez-Lechon, M. J.; Pfeifer, A.; Castell, J. Hepatic Metabolism of Diclofenac: Role of Human CYP in the Minor Oxidative Pathways Biochem. Pharmacol. 1999, 58, 787-796
85. Mancy, A.; Broto, P.; Dijols, S.; Dansette, P. M.; Mansuy, D. The Substrate-Binding Site of Human Liver Cytochrome-P450 2C9-An Approach using Designed Tienilic Acid-Derivatives and Molecular Modeling Biochemistry 1995, 34, 10365-10375
86. Hutzler, J. M.; Balogh, L. M.; Zientek, M.; Kumar, V.; Tracy, T. S. Mechanism-Based Inactivation of Cytochrome P450 2C9 by Tienilic Acid and (±)-Suprofen: A Comparison of Kinetics and Probe Substrate Selection Drug Metab. Dispos. 2009, 37, 59-65