TY - JOUR
T1 - In vitro assessment of the allelic variants of cytochrome P450
AU - Hiratsuka, Masahiro
N1 - Funding Information:
Received August 18, 2011; Accepted September 11, 2011 J-STAGE Advance Published Date: November 1, 2011, doi:10.2133/dmpk.DMPK-11-RV-090 *To whom correspondence should be addressed: Masahiro HIRATSUKA, Ph.D., Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan. Tel. +81-22-717-7049, Fax. +81-22-717-7049, E-mail: mhira@m.tohoku.ac.jp This work was supported by the Japan Society for the Promotion of Science [KAKENHI 23659070], in part by a grant from the Takeda Science Foundation, and the Smoking Research Foundation.
PY - 2012
Y1 - 2012
N2 - Summary: The cytochrome P450 (CYP) superfamily is one of the most important groups of enzymes involved in drug metabolism. It is responsible for the metabolism of a large number of drugs. Many CYP isoforms are expressed polymorphically, and catalytic alterations of allelic variant proteins can affect the metabolic activities of many drugs. The CYP2D6, CYP2C9, CYP2C19, and CYP2B6 genes are particularly polymorphic, whereas CYP1A1, CYP1A2, CYP2E1, and CYP3A4 are relatively well conserved without common functional polymorphisms. In vitro studies using cDNA expression systems are useful tools for evaluating functional alterations of the allelic variants of CYP, particularly for low-frequency alleles. Recombinant CYPs have been successfully expressed in bacteria, yeast, baculoviruses, and several mammalian cells. Determination of CYP variant-mediated kinetic parameters (Km and Vmax) in vitro can be useful for predicting drug dosing and clearance in humans. This review focuses on the advantages and disadvantages of the various cDNA-expression systems used to determine the kinetic parameters for CYP allelic variants, the methods for determining the kinetic parameters, and the findings of in vitro studies on highly polymorphic CYPs, including CYP2D6, CYP2C9, CYP2C19, and CYP2B6.
AB - Summary: The cytochrome P450 (CYP) superfamily is one of the most important groups of enzymes involved in drug metabolism. It is responsible for the metabolism of a large number of drugs. Many CYP isoforms are expressed polymorphically, and catalytic alterations of allelic variant proteins can affect the metabolic activities of many drugs. The CYP2D6, CYP2C9, CYP2C19, and CYP2B6 genes are particularly polymorphic, whereas CYP1A1, CYP1A2, CYP2E1, and CYP3A4 are relatively well conserved without common functional polymorphisms. In vitro studies using cDNA expression systems are useful tools for evaluating functional alterations of the allelic variants of CYP, particularly for low-frequency alleles. Recombinant CYPs have been successfully expressed in bacteria, yeast, baculoviruses, and several mammalian cells. Determination of CYP variant-mediated kinetic parameters (Km and Vmax) in vitro can be useful for predicting drug dosing and clearance in humans. This review focuses on the advantages and disadvantages of the various cDNA-expression systems used to determine the kinetic parameters for CYP allelic variants, the methods for determining the kinetic parameters, and the findings of in vitro studies on highly polymorphic CYPs, including CYP2D6, CYP2C9, CYP2C19, and CYP2B6.
KW - Allelic variant
KW - Cytochrome P450
KW - Genetic polymorphism
KW - In vitro
KW - Kinetic parameter
KW - Pharmacogenetics
KW - SNP
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U2 - 10.2133/dmpk.DMPK-11-RV-090
DO - 10.2133/dmpk.DMPK-11-RV-090
M3 - Review article
C2 - 22041138
AN - SCOPUS:84857705942
VL - 27
SP - 68
EP - 84
JO - Drug Metabolism and Pharmacokinetics
JF - Drug Metabolism and Pharmacokinetics
SN - 1347-4367
IS - 1
ER -