![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Received for publication July 13, 2004.
Revised September 13, 2004.
Accepted for publication September 14, 2004.
Cytochrome P450 3A4 and 3A5 exhibit significant overlap in substrate specificity, but can differ in product regioselectivity and formation activity. To further explore this issue, we compared the kinetics of product formation for eight different substrates, using heterologously expressed CYP3A4 and CYP3A5 and phenotyped human liver microsomes. Both enzymes displayed allosteric behavior towards six of the substrates. When it occurred, the "maximal" intrinsic clearance was used for quantitative comparisons. Based on this parameter, CYP3A5 was more active than CYP3A4 in catalyzing total midazolam hydroxylation (3-fold) and lidocaine demethylation (1.4-fold). CYP3A5 exhibited comparable metabolic activity as CYP3A4 (88 - 110%) towards dextromethorphan N-demethylation, and carbamazepine epoxidation. CYP3A5-catalyzed erythromycin N-demethylation, total flunitrazepam hydroxylation, testosterone 6
-hydroxylation, and terfenadine alcohol formation occurred with an intrinsic clearance that was less than 65% that of CYP3A4. Using two sets of human liver microsomes with equivalent CYP3A4-specific content but markedly different CYP3A5 content (group 1: predominantly CYP3A4; group 2: CYP3A4+CYP3A5), we assessed the contribution of CYP3A5 to product formation rates determined at low substrate concentrations (
Km). Mean product formation rates for group 2 microsomes were 1.4- to 2.2-fold higher than those of group 1 microsomes (p < 0.05 for 5 of 8 substrates). After adjusting for CYP3A4 activity (itraconazole hydroxylation), mean product formation rates for Group 2 microsomes were still significantly higher than those of Group 1 microsomes (p < 0.05 for 3 substrates). We sugest that, under conditions when CYP3A5 content represents a significant fraction of the total hepatic CYP3A pool, CYP3A5's contribution to the clearance of some drugs may be an important source of interindividual variability.
Key words:
CYP3A, genetic polymorphism, pharmacogenetics
This article has been cited by other articles:
|
|
 |
|
  J. B. Dennison, M. A. Mohutsky, R. J. Barbuch, S. A. Wrighton, and S. D. Hall Apparent High CYP3A5 Expression Is Required for Significant Metabolism of Vincristine by Human Cryopreserved Hepatocytes J. Pharmacol. Exp. Ther., October 1, 2008; 327(1): 248 - 257. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Henshall, A. Galetin, A. Harrison, and J. B. Houston Comparative Analysis of CYP3A Heteroactivation by Steroid Hormones and Flavonoids in Different in Vitro Systems and Potential in Vivo Implications Drug Metab. Dispos., July 1, 2008; 36(7): 1332 - 1340. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-Y. Ku, H.-J. Ahn, K.-A. Seo, H. Kim, M. Oh, S. K. Bae, J.-G. Shin, J.-H. Shon, and K.-H. Liu The Contributions of Cytochromes P450 3A4 and 3A5 to the Metabolism of the Phosphodiesterase Type 5 Inhibitors Sildenafil, Udenafil, and Vardenafil Drug Metab. Dispos., June 1, 2008; 36(6): 986 - 990. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Isoherranen, S. R. Ludington, R. C. Givens, J. K. Lamba, S. N. Pusek, E. C. Dees, D. K. Blough, K. Iwanaga, R. L. Hawke, E. G. Schuetz, et al. The Influence of CYP3A5 Expression on the Extent of Hepatic CYP3A Inhibition Is Substrate-Dependent: An in Vitro-in Vivo Evaluation Drug Metab. Dispos., January 1, 2008; 36(1): 146 - 154. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Ma, S. L. Polsky-Fisher, S. Vickers, D. Cui, and A. D. Rodrigues Cytochrome P450 3A-Dependent Metabolism of a Potent and Selective {gamma}-Aminobutyric AcidA{alpha}2/3 Receptor Agonist in Vitro: Involvement of Cytochrome P450 3A5 Displaying Biphasic Kinetics Drug Metab. Dispos., August 1, 2007; 35(8): 1301 - 1307. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Watanabe, K. Nakamura, N. Okudaira, O. Okazaki, and K.-i. Sudo Risk Assessment for Drug-Drug Interaction Caused by Metabolism-Based Inhibition of CYP3A Using Automated in Vitro Assay Systems and Its Application in the Early Drug Discovery Process Drug Metab. Dispos., July 1, 2007; 35(7): 1232 - 1238. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Zhao, C. A. Lee, and K. L. Kunze Sequential Metabolism Is Responsible for Diltiazem-Induced Time-Dependent Loss of CYP3A Drug Metab. Dispos., May 1, 2007; 35(5): 704 - 712. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. B. Dennison, D. R. Jones, J. L. Renbarger, and S. D. Hall Effect of CYP3A5 Expression on Vincristine Metabolism with Human Liver Microsomes J. Pharmacol. Exp. Ther., May 1, 2007; 321(2): 553 - 563. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-l. Lin and P. F. Hollenberg The Inactivation of Cytochrome P450 3A5 by 17{alpha}-Ethynylestradiol Is Cytochrome b5-Dependent: Metabolic Activation of the Ethynyl Moiety Leads to the Formation of Glutathione Conjugates, a Heme Adduct, and Covalent Binding to the Apoprotein J. Pharmacol. Exp. Ther., April 1, 2007; 321(1): 276 - 287. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Totah, K. E. Allen, P. Sheffels, D. Whittington, and E. D. Kharasch Enantiomeric Metabolic Interactions and Stereoselective Human Methadone Metabolism J. Pharmacol. Exp. Ther., April 1, 2007; 321(1): 389 - 399. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. O'Donnell, K. Grime, P. Courtney, D. Slee, and R. J. Riley The Development of a Cocktail CYP2B6, CYP2C8, and CYP3A5 Inhibition Assay and a Preliminary Assessment of Utility in a Drug Discovery Setting Drug Metab. Dispos., March 1, 2007; 35(3): 381 - 385. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Shao, P. L. Stapleton, Y. S. Lin, and E. P. Gallagher Cytochrome P450 and Glutathione S-Transferase mRNA Expression in Human Fetal Liver Hematopoietic Stem Cells Drug Metab. Dispos., January 1, 2007; 35(1): 168 - 175. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. B. Dennison, P. Kulanthaivel, R. J. Barbuch, J. L. Renbarger, W. J. Ehlhardt, and S. D. Hall SELECTIVE METABOLISM OF VINCRISTINE IN VITRO BY CYP3A5 Drug Metab. Dispos., August 1, 2006; 34(8): 1317 - 1327. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Dai, M. F. Hebert, N. Isoherranen, C. L. Davis, C. Marsh, D. D. Shen, and K. E. Thummel EFFECT OF CYP3A5 POLYMORPHISM ON TACROLIMUS METABOLIC CLEARANCE IN VITRO Drug Metab. Dispos., May 1, 2006; 34(5): 836 - 847. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-J. Lee, W. J. Jusko, C. G. Salaita, K. A. Calis, M. W. Jann, V. E. Spratlin, J. A. Goldstein, and Y. Y. Hon Reduced Methylprednisolone Clearance Causing Prolonged Pharmacodynamics in a Healthy Subject Was Not Associated With CYP3A5*3 Allele or a Change in Diet Composition. J. Clin. Pharmacol., May 1, 2006; 46(5): 515 - 526. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Busi and T. Cresteil CYP3A5 mRNA Degradation by Nonsense-Mediated mRNA Decay Mol. Pharmacol., September 1, 2005; 68(3): 808 - 815. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. K. Kamdem, F. Streit, U. M. Zanger, J. Brockmoller, M. Oellerich, V. W. Armstrong, and L. Wojnowski Contribution of CYP3A5 to the in Vitro Hepatic Clearance of Tacrolimus Clin. Chem., August 1, 2005; 51(8): 1374 - 1381. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. McCune, L. J. Risler, B. R. Phillips, K. E. Thummel, D. Blough, and D. D. Shen CONTRIBUTION OF CYP3A5 TO HEPATIC AND RENAL IFOSFAMIDE N-DECHLOROETHYLATION Drug Metab. Dispos., July 1, 2005; 33(7): 1074 - 1081. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Galetin, K. Ito, D. Hallifax, and J. B. Houston CYP3A4 Substrate Selection and Substitution in the Prediction of Potential Drug-Drug Interactions J. Pharmacol. Exp. Ther., July 1, 2005; 314(1): 180 - 190. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Picard, T. Cresteil, N. Djebli, and P. Marquet IN VITRO METABOLISM STUDY OF BUPRENORPHINE: EVIDENCE FOR NEW METABOLIC PATHWAYS Drug Metab. Dispos., May 1, 2005; 33(5): 689 - 695. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
