Genetic Differences in Enzymes which Metabolize Drugs, Chemical Carcinogens, and Other Environmental Pollutants

  • Daniel W. Nebert
  • Masahiko Negishi
  • Howard J. Eisen
Part of the Environmental Science Research book series (ESRH, volume 26)

Abstract

In the literature dozens of examples exist in which gene differences are reflected as variations in individual risk of cancer or pharmacologic response. One of the most well-characterized is the Ah locus, which controls the induction of a group of drug-metabolizing enzymes by polycyclic aromatic compounds such as 2,3,7,8-tetrachloro- dibenzo-p-dioxin (TCDD) and 3-methylcholanthrene. While studying this genetic system, we have examined the effects of TCDD in cell culture and the metabolism of TCDD by mouse liver microsomes in vitro. The principal genetic defect among certain inbred mouse strains involves a cytosolic receptor for TCDD. The level of receptor has been shown in mice and perhaps in man to reflect individual differences in risk of certain chemically induced cancers, mutations, drug toxicities, and birth defects.

With one of the structural genes (cytochrome P1-450) of the Ah locus, recently cloned in this laboratory, we hope to understand the genetic regulation of P-450 induction and the evolution of this enzyme system which responds to various adverse environmental chemicals. We hope to develop sensitive clinical assays for predicting individual genetic differences in risk of cancer, drug toxicity, and birth defects caused by certain environmental pollutants.

Keywords

Toxicity Leukemia Hydrocarbon Retina NADPH 

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Copyright information

© Plenum Press, New York 1983

Authors and Affiliations

  • Daniel W. Nebert
    • 1
  • Masahiko Negishi
    • 1
  • Howard J. Eisen
    • 1
  1. 1.National Institute of Child Health and Human Development National Institutes of HealthBethesdaUSA

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