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Effects of environmental chemicals on the genetic regulation of microsomal enzyme systems
Author(s) -
Nebert Daniel W.,
Levitt Roy C.,
Orlando Michael M.,
Felton James S.
Publication year - 1977
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt1977225part2640
Subject(s) - mutagenesis , toxicity , context (archaeology) , carcinogen , monooxygenase , cytochrome p450 , carcinogenesis , drug metabolism , biology , detoxification (alternative medicine) , mutation , genetic predisposition , genetics , chemistry , biochemistry , pharmacology , toxicology , metabolism , gene , medicine , paleontology , alternative medicine , organic chemistry , pathology
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‐acetylaminojiuorene, and acetaminophen in inbred strains of mice and in genetic crosses. Only a very small number of genes was found to have a profound injiuence 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.