Effects of environmental chemicals on the genetic regulation of microsomal enzyme systems

Daniel W. Nebert, Roy C. Levitt, Michael M. Orlando, James S. Felton

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

The cytochrome P-450-mediated monooxygenase system, embedded in the endoplasmic reticulum of cell membranes, which metabolizes many hydrophobic environmental chemicals is involved in the metabolic potentiation and/or detoxification of many drugs and environmental pollutants. Examples of the interaction of such environmental chemicals with the genetic regulatory system controlling monooxygenase activity are presented, as well as the manner in which this interaction may be affected by genetic differences in susceptibility to drug toxicity and lead to chemically induced teratogenesis, mutagenesis, and carcinogenesis. Among the chemicals under study in this context were polycyclic hydrocarbons, halogenated hydrocarbons (Arochlor 1254, lindane, kepone), 2-acetylaminoffuorene, and acetaminophen in inbred strains of mice and in genetic crosses. Only a very small number of genes was found to have a profound influence on an individual's increased susceptibility to cancer, mutation, and toxicity produced by different environmental chemicals. Multiphasic response curves are predicted to occur with a given dosage of chemical causing different levels of toxicity in different individuals, depending upon the genetic predisposition of each individual. For example, cancer, chemical mutagenesis, hepatic necrosis, survival time, aplastic anemia, and possibly birth defects can vary among siblings in the same family because a relatively small number of genes regulates the differences in drug metabolism.

Original languageEnglish (US)
Pages (from-to)640-658
Number of pages19
JournalClinical Pharmacology and Therapeutics
Volume22
Issue number5 PART 2
DOIs
StatePublished - Nov 1977
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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