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Modeling Human Cytochrome P450 2D6 Metabolism and Drug-Drug Interaction by a Novel Panel of Knockout and Humanized Mouse Lines

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Modeling Human Cytochrome P450 2D6 Metabolism and Drug-Drug Interaction by a Novel Panel of Knockout and Humanized Mouse Lines. / Scheer, Nico (Lead / Corresponding author); Kapelyukh, Yury; McEwan, Jillian; Beuger, Vincent; Stanley, Lesley A.; Rode, Anja; Wolf, C. Roland.

In: Molecular Pharmacology, Vol. 81, No. 1, 01.2012, p. 63-72.

Research output: Contribution to journalArticle

Harvard

Scheer, N, Kapelyukh, Y, McEwan, J, Beuger, V, Stanley, LA, Rode, A & Wolf, CR 2012, 'Modeling Human Cytochrome P450 2D6 Metabolism and Drug-Drug Interaction by a Novel Panel of Knockout and Humanized Mouse Lines' Molecular Pharmacology, vol 81, no. 1, pp. 63-72.

APA

Scheer, N., Kapelyukh, Y., McEwan, J., Beuger, V., Stanley, L. A., Rode, A., & Wolf, C. R. (2012). Modeling Human Cytochrome P450 2D6 Metabolism and Drug-Drug Interaction by a Novel Panel of Knockout and Humanized Mouse Lines. Molecular Pharmacology, 81(1), 63-72doi: 10.1124/mol.111.075192

Vancouver

Scheer N, Kapelyukh Y, McEwan J, Beuger V, Stanley LA, Rode A et al. Modeling Human Cytochrome P450 2D6 Metabolism and Drug-Drug Interaction by a Novel Panel of Knockout and Humanized Mouse Lines. Molecular Pharmacology. 2012 Jan;81(1):63-72.

Author

Scheer, Nico (Lead / Corresponding author); Kapelyukh, Yury; McEwan, Jillian; Beuger, Vincent; Stanley, Lesley A.; Rode, Anja; Wolf, C. Roland / Modeling Human Cytochrome P450 2D6 Metabolism and Drug-Drug Interaction by a Novel Panel of Knockout and Humanized Mouse Lines.

In: Molecular Pharmacology, Vol. 81, No. 1, 01.2012, p. 63-72.

Research output: Contribution to journalArticle

Bibtex - Download

@article{e2eeb9eb6d0049c49833b09908ebdf69,
title = "Modeling Human Cytochrome P450 2D6 Metabolism and Drug-Drug Interaction by a Novel Panel of Knockout and Humanized Mouse Lines",
author = "Nico Scheer and Yury Kapelyukh and Jillian McEwan and Vincent Beuger and Stanley, {Lesley A.} and Anja Rode and Wolf, {C. Roland}",
year = "2012",
volume = "81",
number = "1",
pages = "63--72",
journal = "Molecular Pharmacology",
issn = "0026-895X",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Modeling Human Cytochrome P450 2D6 Metabolism and Drug-Drug Interaction by a Novel Panel of Knockout and Humanized Mouse Lines

A1 - Scheer,Nico

A1 - Kapelyukh,Yury

A1 - McEwan,Jillian

A1 - Beuger,Vincent

A1 - Stanley,Lesley A.

A1 - Rode,Anja

A1 - Wolf,C. Roland

AU - Scheer,Nico

AU - Kapelyukh,Yury

AU - McEwan,Jillian

AU - Beuger,Vincent

AU - Stanley,Lesley A.

AU - Rode,Anja

AU - Wolf,C. Roland

PY - 2012/1

Y1 - 2012/1

N2 - <p>The highly polymorphic human cytochrome P450 2D6 enzyme is involved in the metabolism of up to 25% of all marketed drugs and accounts for significant individual differences in response to CYP2D6 substrates. Because of the differences in the multiplicity and substrate specificity of CYP2D family members among species, it is difficult to predict pathways of human CYP2D6-dependent drug metabolism on the basis of animal studies. To create animal models that reflect the human situation more closely and that allow an in vivo assessment of the consequences of differential CYP2D6 drug metabolism, we have developed a novel straightforward approach to delete the entire murine Cyp2d gene cluster and replace it with allelic variants of human CYP2D6. By using this approach, we have generated mouse lines expressing the two frequent human protein isoforms CYP2D6.1 and CYP2D6.2 and an as yet undescribed variant of this enzyme, as well as a Cyp2d cluster knockout mouse. We demonstrate that the various transgenic mouse lines cover a wide spectrum of different human CYP2D6 metabolizer phenotypes. The novel humanization strategy described here provides a robust approach for the expression of different CYP2D6 allelic variants in transgenic mice and thus can help to evaluate potential CYP2D6-dependent interindividual differences in drug response in the context of personalized medicine.</p>

AB - <p>The highly polymorphic human cytochrome P450 2D6 enzyme is involved in the metabolism of up to 25% of all marketed drugs and accounts for significant individual differences in response to CYP2D6 substrates. Because of the differences in the multiplicity and substrate specificity of CYP2D family members among species, it is difficult to predict pathways of human CYP2D6-dependent drug metabolism on the basis of animal studies. To create animal models that reflect the human situation more closely and that allow an in vivo assessment of the consequences of differential CYP2D6 drug metabolism, we have developed a novel straightforward approach to delete the entire murine Cyp2d gene cluster and replace it with allelic variants of human CYP2D6. By using this approach, we have generated mouse lines expressing the two frequent human protein isoforms CYP2D6.1 and CYP2D6.2 and an as yet undescribed variant of this enzyme, as well as a Cyp2d cluster knockout mouse. We demonstrate that the various transgenic mouse lines cover a wide spectrum of different human CYP2D6 metabolizer phenotypes. The novel humanization strategy described here provides a robust approach for the expression of different CYP2D6 allelic variants in transgenic mice and thus can help to evaluate potential CYP2D6-dependent interindividual differences in drug response in the context of personalized medicine.</p>

KW - HYDROXYLASE-ACTIVITY

KW - HUMAN CYP2D6

KW - HUMAN LIVER

KW - DEBRISOQUINE

KW - GENE

KW - LOCUS

KW - ASSOCIATION

KW - DISPOSITION

KW - POPULATION

KW - EXPRESSION

U2 - 10.1124/mol.111.075192

DO - 10.1124/mol.111.075192

M1 - Article

JO - Molecular Pharmacology

JF - Molecular Pharmacology

SN - 0026-895X

IS - 1

VL - 81

SP - 63

EP - 72

ER -

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