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Transgenic models in xenobiotic metabolism and toxicology

Frank J Gonzalez1

  • 1National Cancer Institute, National Institutes of Health, Building 37, Room 3E-24, Bethesda, MD 20892, USA. fjgonz@helix.nih.gov

Toxicology
|December 31, 2002
PubMed

Insights

Xenobiotic-metabolizing enzymes, like P450s, do not impact mammalian development. However, gene knockout mice lacking these enzymes show resistance to toxins and carcinogens, proving their role in chemical toxicity.

Area of Science:

  • Biochemistry
  • Toxicology
  • Genetics

Background:

  • Animals possess enzymes that metabolize xenobiotics (drugs, toxins, carcinogens).
  • In vitro studies showed these enzymes activate/inactivate toxins, but in vivo roles were unclear.
  • The direct biological impact of xenobiotic metabolism in whole organisms remained to be demonstrated.

Purpose of the Study:

  • To determine the in vivo biological effects of xenobiotic-metabolizing enzymes.
  • To investigate the role of specific enzymes, including P450s and hydrolases, in mediating chemical toxicity and carcinogenesis.
  • To utilize gene knockout animal models to elucidate mechanisms of chemical toxicity.

Main Methods:

  • Generation of gene knockout mice lacking specific xenobiotic-metabolizing enzymes (CYP1A1, CYP1A2, CYP1B1, CYP2E1, microsomal epoxide hydrolase, cytosolic epoxide hydrolase, NADPH:quinone oxidoreductase).
  • Assessment of phenotypes in knockout mice to evaluate developmental and homeostatic roles.
  • Testing the resistance of knockout mice to acute toxicities and chemical carcinogenesis.

Main Results:

  • Mice lacking these xenobiotic-metabolizing enzymes exhibited no deleterious phenotypes, indicating no direct role in development or homeostasis.
  • These knockout mice demonstrated resistance to acute toxicities induced by certain chemicals.
  • Mice deficient in these enzymes showed reduced susceptibility to chemical carcinogenesis.
  • These findings demonstrate that xenobiotic-metabolizing enzymes mediate the harmful effects of toxins and carcinogens.

Conclusions:

  • Xenobiotic-metabolizing enzymes are not essential for mammalian development or physiological homeostasis.
  • These enzymes play a crucial role in mediating the adverse biological effects of xenobiotics, including toxicity and carcinogenicity.
  • Xenobiotic metabolism-null animal models are valuable tools for studying the mechanisms underlying chemical toxicity and carcinogen action.

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