Defining the contribution of CYP1A1 and CYP1A2 to drug metabolism using humanized CYP1A1/1A2 and Cyp1a1/Cyp1a2 KO mice

Yury Kapelyukh, Colin James Henderson, Nico Scheer, Anja Rode, Roland Wolf (Lead / Corresponding author)

Research output: Contribution to journalArticle

Abstract

Animal models are routinely used in drug and chemical safety assessment and in defining the pharmacokinetic/pharmacodynamic properties of drug candidates. The application of models humanised for xenobiotic metabolising enzymes can markedly improve the accuracy of data extrapolation to man. Cytochrome P450s, CYP1A1 and CYP1A2 can metabolize a broad range of foreign compounds and drugs. However, these enzymes have significantly overlapping substrate specificities. In order to establish the relative contribution of these enzymes in drug metabolism in vivo we have used a combination of mice humanized for CYP1A1 and CYP1A2 together with mice nulled at the Cyp1a1 and Cyp1a2 gene loci. Using the differential sensitivity of the human enzymes to the inhibitor quinidine we have developed an enzyme kinetic approach to distinguish the relative role of CYP1A1 or CYP1A2 in drug metabolism. SIGNIFICANCE STATEMENT: Human CYP1A1 and CYP1A2 are important in defining the efficacy and toxicity/carcinogenicity of drugs and foreign compounds. In the light of differences in substrate specificity and sensitivity to inhibitors, it is of central importance to understand their relative role in foreign compound metabolism. To address this issue, we have generated mice humanized or nulled at the Cyp1a gene locus and through the use of these mouse lines and selective inhibitors, developed an enzyme kinetic-based model to enable more accurate prediction of the fate of new chemicals in man, and which can be validated in vivo using mice humanised for cytochrome P450-mediated metabolism.

Original languageEnglish
JournalDrug Metabolism and Disposition
DOIs
Publication statusE-pub ahead of print - 30 May 2019

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Cytochrome P-450 CYP1A2
Cytochrome P-450 CYP1A1
Pharmaceutical Preparations
Enzyme Inhibitors
Enzymes
Substrate Specificity
Chemical Safety
Quinidine
Xenobiotics
Cytochromes
Drug-Related Side Effects and Adverse Reactions
Cytochrome P-450 Enzyme System
Genes
Animal Models
Pharmacokinetics

Keywords

  • cytochrome P450
  • enzyme inhibitors
  • enzyme kinetics
  • genetically modified animal models
  • pharmacokinetic/pharmacodynamic modeling/PKPD
  • pharmacokinetics
  • physiologically-based pharmacokinetic modeling/PBPK

Cite this

@article{41311cd5844e408d8c5bce764ddd2458,
title = "Defining the contribution of CYP1A1 and CYP1A2 to drug metabolism using humanized CYP1A1/1A2 and Cyp1a1/Cyp1a2 KO mice",
abstract = "Animal models are routinely used in drug and chemical safety assessment and in defining the pharmacokinetic/pharmacodynamic properties of drug candidates. The application of models humanised for xenobiotic metabolising enzymes can markedly improve the accuracy of data extrapolation to man. Cytochrome P450s, CYP1A1 and CYP1A2 can metabolize a broad range of foreign compounds and drugs. However, these enzymes have significantly overlapping substrate specificities. In order to establish the relative contribution of these enzymes in drug metabolism in vivo we have used a combination of mice humanized for CYP1A1 and CYP1A2 together with mice nulled at the Cyp1a1 and Cyp1a2 gene loci. Using the differential sensitivity of the human enzymes to the inhibitor quinidine we have developed an enzyme kinetic approach to distinguish the relative role of CYP1A1 or CYP1A2 in drug metabolism. SIGNIFICANCE STATEMENT: Human CYP1A1 and CYP1A2 are important in defining the efficacy and toxicity/carcinogenicity of drugs and foreign compounds. In the light of differences in substrate specificity and sensitivity to inhibitors, it is of central importance to understand their relative role in foreign compound metabolism. To address this issue, we have generated mice humanized or nulled at the Cyp1a gene locus and through the use of these mouse lines and selective inhibitors, developed an enzyme kinetic-based model to enable more accurate prediction of the fate of new chemicals in man, and which can be validated in vivo using mice humanised for cytochrome P450-mediated metabolism.",
keywords = "cytochrome P450, enzyme inhibitors, enzyme kinetics, genetically modified animal models, pharmacokinetic/pharmacodynamic modeling/PKPD, pharmacokinetics, physiologically-based pharmacokinetic modeling/PBPK",
author = "Yury Kapelyukh and Henderson, {Colin James} and Nico Scheer and Anja Rode and Roland Wolf",
note = "Financial support: This research was supported by a Cancer Research UK Programme Grant [C4639/A10822] and Medical Research Council Project Grant MR/R017506/1.",
year = "2019",
month = "5",
day = "30",
doi = "10.1124/dmd.119.087718",
language = "English",
journal = "Drug Metabolism and Disposition",
issn = "0090-9556",
publisher = "American Society for Pharmacology and Experimental Therapeutics",

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TY - JOUR

T1 - Defining the contribution of CYP1A1 and CYP1A2 to drug metabolism using humanized CYP1A1/1A2 and Cyp1a1/Cyp1a2 KO mice

AU - Kapelyukh, Yury

AU - Henderson, Colin James

AU - Scheer, Nico

AU - Rode, Anja

AU - Wolf, Roland

N1 - Financial support: This research was supported by a Cancer Research UK Programme Grant [C4639/A10822] and Medical Research Council Project Grant MR/R017506/1.

PY - 2019/5/30

Y1 - 2019/5/30

N2 - Animal models are routinely used in drug and chemical safety assessment and in defining the pharmacokinetic/pharmacodynamic properties of drug candidates. The application of models humanised for xenobiotic metabolising enzymes can markedly improve the accuracy of data extrapolation to man. Cytochrome P450s, CYP1A1 and CYP1A2 can metabolize a broad range of foreign compounds and drugs. However, these enzymes have significantly overlapping substrate specificities. In order to establish the relative contribution of these enzymes in drug metabolism in vivo we have used a combination of mice humanized for CYP1A1 and CYP1A2 together with mice nulled at the Cyp1a1 and Cyp1a2 gene loci. Using the differential sensitivity of the human enzymes to the inhibitor quinidine we have developed an enzyme kinetic approach to distinguish the relative role of CYP1A1 or CYP1A2 in drug metabolism. SIGNIFICANCE STATEMENT: Human CYP1A1 and CYP1A2 are important in defining the efficacy and toxicity/carcinogenicity of drugs and foreign compounds. In the light of differences in substrate specificity and sensitivity to inhibitors, it is of central importance to understand their relative role in foreign compound metabolism. To address this issue, we have generated mice humanized or nulled at the Cyp1a gene locus and through the use of these mouse lines and selective inhibitors, developed an enzyme kinetic-based model to enable more accurate prediction of the fate of new chemicals in man, and which can be validated in vivo using mice humanised for cytochrome P450-mediated metabolism.

AB - Animal models are routinely used in drug and chemical safety assessment and in defining the pharmacokinetic/pharmacodynamic properties of drug candidates. The application of models humanised for xenobiotic metabolising enzymes can markedly improve the accuracy of data extrapolation to man. Cytochrome P450s, CYP1A1 and CYP1A2 can metabolize a broad range of foreign compounds and drugs. However, these enzymes have significantly overlapping substrate specificities. In order to establish the relative contribution of these enzymes in drug metabolism in vivo we have used a combination of mice humanized for CYP1A1 and CYP1A2 together with mice nulled at the Cyp1a1 and Cyp1a2 gene loci. Using the differential sensitivity of the human enzymes to the inhibitor quinidine we have developed an enzyme kinetic approach to distinguish the relative role of CYP1A1 or CYP1A2 in drug metabolism. SIGNIFICANCE STATEMENT: Human CYP1A1 and CYP1A2 are important in defining the efficacy and toxicity/carcinogenicity of drugs and foreign compounds. In the light of differences in substrate specificity and sensitivity to inhibitors, it is of central importance to understand their relative role in foreign compound metabolism. To address this issue, we have generated mice humanized or nulled at the Cyp1a gene locus and through the use of these mouse lines and selective inhibitors, developed an enzyme kinetic-based model to enable more accurate prediction of the fate of new chemicals in man, and which can be validated in vivo using mice humanised for cytochrome P450-mediated metabolism.

KW - cytochrome P450

KW - enzyme inhibitors

KW - enzyme kinetics

KW - genetically modified animal models

KW - pharmacokinetic/pharmacodynamic modeling/PKPD

KW - pharmacokinetics

KW - physiologically-based pharmacokinetic modeling/PBPK

U2 - 10.1124/dmd.119.087718

DO - 10.1124/dmd.119.087718

M3 - Article

JO - Drug Metabolism and Disposition

JF - Drug Metabolism and Disposition

SN - 0090-9556

ER -