![[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}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (V.L., J.L., K.Y., M.L.H., E.G.S.); Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (S.S.); Pfizer Corp., St. Louis, Missouri (J.D.); Department of Medicine, University of Chicago Medical Center, Chicago, Illinois (J.D.F.); Schools of Medicine and Interdisciplinary Computing and Engineering, University of Missouri, Kansas City, Missouri (P.K.R.); and Eli Lilly & Company, Indianapolis, Indiana (B.R., S.A.W.)
CYP2B6 metabolizes many drugs, and its expression varies greatly. CYP2B6 genotype-phenotype associations were determined using human livers that were biochemically phenotyped for CYP2B6 (mRNA, protein, and CYP2B6 activity), and genotyped for CYP2B6 coding and 5'-flanking regions. CYP2B6 expression differed significantly between sexes. Females had higher amounts of CYP2B6 mRNA (3.9-fold, P < 0.001), protein (1.7-fold, P < 0.009), and activity (1.6-fold, P < 0.05) than did male subjects. Furthermore, 7.1% of females and 20% of males were poor CYP2B6 metabolizers. Striking differences among different ethnic groups were observed: CYP2B6 activity was 3.6- and 5.0-fold higher in Hispanic females than in Caucasian (P < 0.022) or African-American females (P < 0.038). Ten single nucleotide polymorphisms (SNPs) in the CYP2B6 promoter and seven in the coding region were found, including a newly identified 13072A>G substitution that resulted in an Lys139Glu change. Many CYP2B6 splice variants (SV) were observed, and the most common variant lacked exons 4 to 6. A nonsynonymous SNP in exon 4 (15631G>T), which disrupted an exonic splicing enhancer, and a SNP 15582C>T in an intron-3 branch site were correlated with this SV. The extent to which CYP2B6 variation was a predictor of CYP2B6 activity varied according to sex and ethnicity. The 1459C>T SNP, which resulted in the Arg487Cys substitution, was associated with the lowest level of CYP2B6 activity in livers of females. The intron-3 15582C>T SNP (in significant linkage disequilibrium with a SNP in a putative hepatic nuclear factor 4 (HNF4) binding site) was correlated with lower CYP2B6 expression in females. In conclusion, we found several common SNPs that are associated with polymorphic CYP2B6 expression.
Address correspondence to: Dr. Erin G. Schuetz, Department of Pharmaceutical Sciences, Mail Stop 313, St. Jude Children's Research Hospital, 332 N. Lauderdale Street, Memphis, TN 38105. E-mail: erin.schuetz{at}stjude.org
This article has been cited by other articles:
|
|
 |
|
  M. Zhu, S. Kaul, P. Nandy, D. M. Grasela, and M. Pfister Model-Based Approach To Characterize Efavirenz Autoinduction and Concurrent Enzyme Induction with Carbamazepine Antimicrob. Agents Chemother., June 1, 2009; 53(6): 2346 - 2353. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Nishiya, K. Hagihara, T. Ito, M. Tajima, S.-i. Miura, A. Kurihara, N. A. Farid, and T. Ikeda Mechanism-Based Inhibition of Human Cytochrome P450 2B6 by Ticlopidine, Clopidogrel, and the Thiolactone Metabolite of Prasugrel Drug Metab. Dispos., March 1, 2009; 37(3): 589 - 593. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. K. Bae, S. Cao, K.-A. Seo, H. Kim, M.-J. Kim, J.-H. Shon, K.-H. Liu, H.-H. Zhou, and J.-G. Shin Cytochrome P450 2B6 Catalyzes the Formation of Pharmacologically Active Sibutramine (N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N,N-dimethylamine) Metabolites in Human Liver Microsomes Drug Metab. Dispos., August 1, 2008; 36(8): 1679 - 1688. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Hashita, T. Sakuma, M. Akada, A. Nakajima, H. Yamahara, S. Ito, H. Takesako, and N. Nemoto Forkhead Box A2-Mediated Regulation of Female-Predominant Expression of the Mouse Cyp2b9 Gene Drug Metab. Dispos., June 1, 2008; 36(6): 1080 - 1087. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. G. Holloway, G. D. Miles, A. A. Dombkowski, and D. J. Waxman Liver-Specific Hepatocyte Nuclear Factor-4{alpha} Deficiency: Greater Impact on Gene Expression in Male than in Female Mouse Liver Mol. Endocrinol., May 1, 2008; 22(5): 1274 - 1286. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. H. Hofmann, J. K. Blievernicht, K. Klein, T. Saussele, E. Schaeffeler, M. Schwab, and U. M. Zanger 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., April 1, 2008; 325(1): 284 - 292. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Lamba, V. Lamba, S. Strom, R. Venkataramanan, and E. Schuetz Novel Single Nucleotide Polymorphisms in the Promoter and Intron 1 of Human Pregnane X Receptor/NR1I2 and Their Association with CYP3A4 Expression Drug Metab. Dispos., January 1, 2008; 36(1): 169 - 181. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Wortham, M. Czerwinski, L. He, A. Parkinson, and Y.-J. Y. Wan Expression of Constitutive Androstane Receptor, Hepatic Nuclear Factor 4{alpha}, and P450 Oxidoreductase Genes Determines Interindividual Variability in Basal Expression and Activity of a Broad Scope of Xenobiotic Metabolism Genes in the Human Liver Drug Metab. Dispos., September 1, 2007; 35(9): 1700 - 1710. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. E. Estes, K. H. Busse, and S. R. Penzak Pharmacogenetic Considerations in the Management of HIV Infection Journal of Pharmacy Practice, June 1, 2007; 20(3): 234 - 245. [Abstract] [PDF]
|
|
|
|
 |
|
 J. K. Blievernicht, E. Schaeffeler, K. Klein, M. Eichelbaum, M. Schwab, and U. M. Zanger MALDI-TOF Mass Spectrometry for Multiplex Genotyping of CYP2B6 Single-Nucleotide Polymorphisms Clin. Chem., January 1, 2007; 53(1): 24 - 33. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. L. Walsky, A. V. Astuccio, and R. S. Obach Evaluation of 227 Drugs for In Vitro Inhibition of Cytochrome P450 2B6. J. Clin. Pharmacol., December 1, 2006; 46(12): 1426 - 1438. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Waxman and C. O'Connor Growth Hormone Regulation of Sex-Dependent Liver Gene Expression Mol. Endocrinol., November 1, 2006; 20(11): 2613 - 2629. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Sugatani, T. Wada, M. Osabe, K. Yamakawa, K. Yoshinari, and M. Miwa Dietary Inulin Alleviates Hepatic Steatosis and Xenobiotics-Induced Liver Injury in Rats Fed a High-Fat and High-Sucrose Diet: Association with the Suppression of Hepatic Cytochrome P450 and Hepatocyte Nuclear Factor 4{alpha} Expression Drug Metab. Dispos., October 1, 2006; 34(10): 1677 - 1687. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Lee and R. F. Tyndale Drugs and genotypes: how pharmacogenetic information could improve smoking cessation treatment J Psychopharmacol, July 1, 2006; 20(4_suppl): 7 - 14. [Abstract] [PDF]
|
|
|
|
|
|
J. L. F. Rehmel, J. A. Eckstein, N. A. Farid, J. B. Heim, S. C. Kasper, A. Kurihara, S. A. Wrighton, and B. J. Ring INTERACTIONS OF TWO MAJOR METABOLITES OF PRASUGREL, A THIENOPYRIDINE ANTIPLATELET AGENT, WITH THE CYTOCHROMES P450 Drug Metab. Dispos., April 1, 2006; 34(4): 600 - 607. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. G. Holloway, E. V. Laz, and D. J. Waxman Codependence of Growth Hormone-Responsive, Sexually Dimorphic Hepatic Gene Expression on Signal Transducer and Activator of Transcription 5b and Hepatic Nuclear Factor 4{alpha} Mol. Endocrinol., March 1, 2006; 20(3): 647 - 660. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Zukunft, T. Lang, T. Richter, K. I. Hirsch-Ernst, A. K. Nussler, K. Klein, M. Schwab, M. Eichelbaum, and U. M. Zanger A Natural CYP2B6 TATA Box Polymorphism (-82T-> C) Leading to Enhanced Transcription and Relocation of the Transcriptional Start Site Mol. Pharmacol., May 1, 2005; 67(5): 1772 - 1782. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Hukkanen, P. Jacob III, and N. L. Benowitz Metabolism and Disposition Kinetics of Nicotine Pharmacol. Rev., March 1, 2005; 57(1): 79 - 115. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Qatanani, J. Zhang, and D. D. Moore Role of the Constitutive Androstane Receptor in Xenobiotic-Induced Thyroid Hormone Metabolism Endocrinology, March 1, 2005; 146(3): 995 - 1002. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. A. Wiwi and D. J. Waxman Role of Hepatocyte Nuclear Factors in Transcriptional Regulation of Male-specific CYP2A2 J. Biol. Chem., February 4, 2005; 280(5): 3259 - 3268. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Obach, L. M. Cox, and L. M. Tremaine SERTRALINE IS METABOLIZED BY MULTIPLE CYTOCHROME P450 ENZYMES, MONOAMINE OXIDASES, AND GLUCURONYL TRANSFERASES IN HUMAN: AN IN VITRO STUDY Drug Metab. Dispos., February 1, 2005; 33(2): 262 - 270. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-Y. Cho, H.-S. Lim, J.-Y. Chung, K.-S. Yu, J.-R. Kim, S.-G. Shin, and I.-J. Jang HAPLOTYPE STRUCTURE AND ALLELE FREQUENCIES OF CYP2B6 IN A KOREAN POPULATION Drug Metab. Dispos., December 1, 2004; 32(12): 1341 - 1344. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. K. Lamba, V. Lamba, K. Yasuda, Y. S. Lin, M. Assem, E. Thompson, S. Strom, and E. Schuetz Expression of Constitutive Androstane Receptor Splice Variants in Human Tissues and Their Functional Consequences J. Pharmacol. Exp. Ther., November 1, 2004; 311(2): 811 - 821. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Lang, K. Klein, T. Richter, A. Zibat, R. Kerb, M. Eichelbaum, M. Schwab, and U. M. Zanger Multiple Novel Nonsynonymous CYP2B6 Gene Polymorphisms in Caucasians: Demonstration of Phenotypic Null Alleles J. Pharmacol. Exp. Ther., October 1, 2004; 311(1): 34 - 43. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Zhang, M. Caggana, T. L. Cutler, and X. Ding Development of a Real-Time Polymerase Chain Reaction-Based Method for the Measurement of Relative Allelic Expression and Identification of CYP2A13 Alleles with Decreased Expression in Human Lung J. Pharmacol. Exp. Ther., October 1, 2004; 311(1): 373 - 381. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Ramirez, F. Innocenti, E. G. Schuetz, D. A. Flockhart, M. V. Relling, R. Santucci, and M. J. Ratain CYP2B6, CYP3A4, AND CYP2C19 ARE RESPONSIBLE FOR THE IN VITRO N-DEMETHYLATION OF MEPERIDINE IN HUMAN LIVER MICROSOMES Drug Metab. Dispos., September 1, 2004; 32(9): 930 - 936. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Futatsugawa, T. Kubota, A. Ishiguro, H. Suzuki, H. Ishikawa, and T. Iga PCR-Based Haplotype Determination to Distinguish CYP2B6*1/*7 and *5/*6 Clin. Chem., August 1, 2004; 50(8): 1472 - 1473. [Full Text] [PDF]
|
|
|
|
|
|
R. M. Jacob, E. C. Johnstone, M. J. Neville, and R. T. Walton Identification of CYP2B6 Sequence Variants by Use of Multiplex PCR with Allele-Specific Genotyping Clin. Chem., August 1, 2004; 50(8): 1372 - 1377. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
