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Genetically modified mouse models for pharmacogenomic research

Nature Reviews Genetics volume 5, pages 657–663 (2004)Cite this article

Abstract

It is now evident that differences in the DNA sequence of genes involved with drug action can lead to interindividual differences in effectiveness and adverse reactions to therapeutic drugs. Pharmacogenomics raises the possibility that drug discovery and patient management could move from a 'one drug fits all' approach to one in which therapy is tailored to patients' genomes. Genetically modified mice that mimic human variation in drug response can provide one of the tools to move the field towards these goals.

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Figure 1: β1-Adrenergic receptor (β1AR) polymorphisms influence cardiac function and the response to β-agonist and antagonist.
Figure 2: β1-Adrenergic receptor (β1AR) genotype and the clinical response to β-blockers.

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Acknowledgements

Supported by National Institutes of Health grants.

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Authors and Affiliations

  1. University of Cincinnati College of Medicine, 231 Albert Sabin Way, Room G062, Cincinnati, 45267-0564, Ohio, United States

    Stephen B. Liggett

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  1. Stephen B. Liggett
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DATABASES

Entrez Gene

ADRB1

ADRB2

CFTR

CYP1A2

CYP2D6

CYP2E1

CYP3A4

TPMT

OMIM

cystic fibrosis

Glossary

ACETAMINOPHEN

A non-prescription drug that is used to reduce fever and pain. Increased blood levels from overdose or altered metabolism can cause liver disease.

BRONCHOSCOPY

A procedure in which a cylindrical fiberoptic scope is inserted into the airways. This scope contains a viewing device that allows the visual examination of the airways and channels for specimen retrieval.

CARDIAC EJECTION FRACTION

The portion of blood that is pumped out of a filled ventricle as a result of a contraction.

CARDIOMYOCYTES

Heart muscle cells.

CATECHOLAMINES

The endogenous agonists (adrenaline and noradrenaline) for adrenergic receptors, which act as neurotransmitters and hormones.

CYTOCHROME P450

A family of enzymes that act in various metabolic pathways, including inactivation of toxins. In addition, these enzymes can metabolize therapeutic drugs that affect activity and clearance.

DEBRISOQUINE

An antihypertensive agent that is used as a benchmark agent in cytochrome P450 drug metabolism studies.

DILATED CARDIOMYOPATHY

A disease of the heart that is characterized by dilated cardiac chambers and decreased pumping function. This is one of the most common forms of congestive heart failure.

EXTENSIVE METABOLIZERS

An individual who metabolizes a substance at an accelerated rate or extent as compared with that of a reference population.

LINKAGE DISEQUILIBRIUM

The occurence together on the same chromosome of specific alleles at closely linked loci more frequently than would be expected by chance.

MIDAZOLAM

A drug that is used to promote sleepiness and reduce anxiety. It is also used as a benchmark agent in cytochrome P450 drug metabolism studies.

NEPHROGENIC DIABETES INSIPIDUS

A congenital condition that is characterized by the passage of large volumes of urine owing to a defect of the kidney tubules.

POLYMORPHISM

A variation in DNA sequence that occurs at an allele frequency ≥ 1% in a population. In this definition, the 1% value is arbitrary but well accepted. The nature of the variation, or whether it causes a disease, is not implied.

PSEUDOPREGNANT FEMALES

Females that are mated with vasectomized males. These mice can maintain eggs transferred to them without uterine competition from naturally ovulated eggs.

TACHYPHYLAXIS

A waning of the effects produced by a medication when used on a continuous basis.

TAG-AND-EXCHANGE

A method by which a segment of mouse DNA is removed and replaced by another segment of DNA, such as a mutated form of the mouse segment or a human analogue. The DNA of interest is 'tagged' by selectable markers in a round of gene targeting to isolate the stem cells that have been so altered and to achieve specificity for the replacement.

XENOBIOTICS

Foreign compounds that are taken up by the body. These include natural substances, therapeutic drugs and environmental toxins.

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Liggett, S. Genetically modified mouse models for pharmacogenomic research. Nat Rev Genet 5, 657–663 (2004). https://doi.org/10.1038/nrg1429

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