Genetic aspects of toxicity during development.

The Ah locus in the mouse controls the induction of cytochrome P1-450 and at least eleven associated monooxygenase activities. These enzyme systems metabolically potentiate and detoxify drugs, environmental pollutants, and other foreign chemicals, as well as numerous endogenous substrates. For certain substrates, it is known that cytochrome P1-450 produces different reactive intermediates and products that other forms of P-450. Alleles at the Ah locus can be identified in utero. Development toxicity (in the form of stillborns, resorptions, and malformations of the fetus) by 3-methylcholanthrene and 7,12-dimethylbenz[a]anthracene given to the pregnant mother is associated with genetically mediated aromatic hydrocarbon responsiveness in C5BL/6N mice, compared with that in nonresponsive AKR/N mice. Acetaminiphen-produced hepatic necrosis is associated with glutathione depletion in the liver, covalent binding of metabolite(s) of the drug to cellular macromolecules, and P1-450 induction controlled by the Ah locus. For reasons not known, the fetus and mice 10 days of age or less are relatively resistant to glutathione depletion and therefore hepatic necrosis by acetaminophen.