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Understanding Molecular Mechanisms of Toxicity and Carcinogenicity Using Gene Knockout and Transgenic Mouse Models

  • Chapter
Transgenic Models in Pharmacology

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 159))

  • 126 Accesses

Abstract

An exponential increase of new chemical agents came with the industrial revolution. Since then, thousands of new compounds have been released to the environment with an important negative impact on human health. Understanding the mechanisms by which xenobiotics induce toxicity is crucial to prevent potential health hazards. However, the complex mechanism of action of chemical toxins has made it extremely difficult to evaluate the precise toxic mechanism as well as the role of specific genes in either potentiating or ameliorating toxicity. Among the different strategies, the problem can be addressed with genetically engineered animal models where genes have been manipulated to study their roles in chemical toxicity. Xenobiotic-metabolizing enzymes and xenobiotic receptors are considered the interface between chemicals and the environment. In particular, the cytochromes P450 (P450) have an important role in metabolic activation and detoxification of xenobiotics through oxidative metabolism. P450s can activate inert compounds to electrophilic derivatives that are capable of damaging and transforming cells. Other enzymes such as the various transferases can inactivate reactive intermediates. Xenobiotic receptors including the aryl hydrocarbon receptor (AHR), peroxisome proliferator-activated receptor α (PPARα), pregnane X receptor (PXR), and constitutively androstane receptor (CAR), which bind to foreign chemicals and induce enzymes, including P450s, responsible for metabolizing xenobiotics. The study of the roles of P450s and receptors in toxicity and carcinogenicity has been complicated by the marked species differences in these enzymes, making the prediction of human toxicity based on rodent data difficult. During the past seven years, several lines of xenobiotic metabolism-null mice have been produced to address the role of P450s and xenobiotic receptors in whole animal carcinogenesis and toxicity. More recently, humanized mouse models have been developed to aid in human risk assessment to toxic chemicals. The use of transgenic models should lead to a much greater understanding of potential risks associated with exposure to xenobiotics.

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Authors and Affiliations

  1. Sección Externa de Toxicología, CINVESTAV-IPN, PO Box 14-740, 07000, México, D.F., México

    G. Elizondo

  2. National Institutes of Health, Building 37, Room 3E-24, 9000 Rockville Pike, Bethesda, MD, 20892, USA

    F. J. Gonzalez

Authors
  1. G. Elizondo
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  2. F. J. Gonzalez
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Editors and Affiliations

  1. Pharmakologisches Institut, Universität Heidelberg, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany

    Stefan Offermanns

  2. Institut für Pharmakologie und Toxikologie der Universität, Versbacher Straße 9, 97078, Germany

    Lutz Hein

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© 2004 Springer-Verlag Berlin Heidelberg

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Elizondo, G., Gonzalez, F.J. (2004). Understanding Molecular Mechanisms of Toxicity and Carcinogenicity Using Gene Knockout and Transgenic Mouse Models. In: Offermanns, S., Hein, L. (eds) Transgenic Models in Pharmacology. Handbook of Experimental Pharmacology, vol 159. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-18934-0_21

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  • DOI: https://doi.org/10.1007/978-3-642-18934-0_21

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-62362-2

  • Online ISBN: 978-3-642-18934-0

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