How knockout mouse lineswill be used to study the role of drug-metabolizing enzymes and their receptors during reproduction and development, and in environmental toxicity, Cancer, and Oxidative stress

doi:10.1016/S0006-2952(96)00740-X

Biochemical Pharmacology

Volume 53, Issue 3, 7 February 1997, Pages 249-254

https://doi.org/10.1016/S0006-2952(96)00740-X Get rights and content

Abstract

The dioxin-inducible mouse [Ah] battery contains at least six genes that “cross-talk” with one another and are believed to play important roles in reproduction and development, and in environmental toxicity, cancer, and oxidative stress. In addition to two P450 genes, Cyp1a1 and Cyp1a2, this laboratory has shown that the four Phase II [Ah] genes include: NAD(P)H:menadione oxidoreductase (Nmo1); a cytosolic “class 3” aldehyde dehydrogenase (Ahd4); a UDP glucuronosyltransferase having 4-methylumbelliferone as substrate (Ugt1a6); and a glutathione transferase having 2,4-dinitro-1-chlorobenzene as substrate (Gsta1, Ya). The Ah receptor-mediated coordinate induction is controlled positively in all six [Ah] battery genes. Oxidative stress up-regulates the four Phase II [Ah] genes. This laboratory is generating conventional, plus inducible, knockout mouse lines having homozygous disruptions in the above-mentioned genes; this novel methodology is described herein. If the conventional knockout is healthy and viable, the mouse line would be useful for studies involving environmental agents. If the conventional knockout is lethal during development, this model would be important for developmental biology, but the inducible (also called conditional) knockout can still be used—at selected ages and even in selected tissue or cell types—for studies designed to understand the mechanisms involved in reproduction and development, and in environmental toxicity, cancer, and oxidative stress.

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^☆: This work was supported, in part, by NIH Grants R01 AG09235, R01 ES06321, R01 ES06811, R01 ES07058, R01 ES08147, and P30 ES06096.

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CommentaryHow knockout mouse lineswill be used to study the role of drug-metabolizing enzymes and their receptors during reproduction and development, and in environmental toxicity, Cancer, and Oxidative stress☆

Abstract

Trends Genet

Biochem Pharmacol

Biochem Pharmacol

Cell

J Biol Chem

Trends Genet

Cell

Trends Genet

Trends Biochem Sci

Trends Genet

Cell

Noradrenaline is essential for mouse fetal development

Nature

Targeted disruption of the tyrosine hydroxylase gene reveals that catecholamines are required for mouse fetal development

Nature

Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele

Nature

Targeted mutation of Ncam to produce a secreted molecule results in a dominant embryonic lethality

The Ah locus: Genetic differences in toxicity, cancer, mutation, and birth defects

Crit Rev Toxicol

Role of the Ah receptor and the dioxin-inducible [Ah] gene battery in toxicity, cancer, and signal transduction

Ann NY Acad Sci

Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor

Science

Early-onset multifocal inflammation in the transforming growth factor β1-null mouse is lymphocyte mediated

Deletion of a DNA polymerase β gene segment in T cells using cell type-specific gene targeting

Science

Generation of mice with a 200-kb amyloid precursor protein gene deletion by Cre recombinase-mediated site-specific recombination in embryonic stem cells

Cre-medited site-specific translocation between nonhomologous mouse chromosomes

Commentary
How knockout mouse lineswill be used to study the role of drug-metabolizing enzymes and their receptors during reproduction and development, and in environmental toxicity, Cancer, and Oxidative stress☆