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Generation and characterization of novel cytochrome P450 Cyp2c gene cluster knockout and CYP2C9 humanized mouse lines

Nico Scheer1, Yury Kapelyukh, Lynsey Chatham

  • 1TaconicArtemis, Koeln, Germany. nico.scheer@taconicartemis.com

Molecular Pharmacology
|August 25, 2012
PubMed

Insights

Human cytochrome P450 (CYP450) gene clusters differ from rodents, limiting animal models for drug metabolism studies. New mouse models with Cyp2c gene deletion and humanized CYP2C9 expression offer powerful research tools.

Area of Science:

  • Pharmacology
  • Genetics
  • Biochemistry

Background:

  • Human cytochrome P450 (CYP450) Cyp2c gene clusters exhibit significant variation in gene number and enzyme substrate specificity compared to other species.
  • This variability limits the predictive accuracy of traditional animal models for human CYP2C enzyme activity in drug metabolism and drug-drug interactions.
  • Human CYP2C9 is a key enzyme in liver metabolism for numerous drugs and environmental chemicals.

Purpose of the Study:

  • To investigate the in vivo functions of cytochrome P450 Cyp2c genes.
  • To develop a mouse model for studying CYP2C9 function in vivo.
  • To create a humanized mouse model expressing CYP2C9 specifically in the liver.

Main Methods:

  • Generation of a mouse model with a deletion of the entire murine Cyp2c gene cluster.
  • Development of a corresponding humanized mouse model expressing human CYP2C9 in the liver.
  • Phenotypic analysis of mice with Cyp2c gene deletion and humanized CYP2C9 expression.

Main Results:

  • Mice with Cyp2c gene cluster deletion were viable and fertile, exhibiting specific liver phenotypic alterations.
  • The humanized mouse model successfully expressed CYP2C9 in the liver.
  • The humanized mice demonstrated activity in the metabolism and disposition of CYP2C9 substrates.

Conclusions:

  • The generated mouse lines are valuable tools for studying Cyp2c gene functions in vivo.
  • These models are crucial for understanding the role of CYP2C9 in drug disposition and drug-drug interactions.
  • The models facilitate research into species-specific differences in drug metabolism.

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