Importance of genetic factors influencing the metabolism of foreign compounds.

Gene differences may alter an individual's response to foreign compounds by affecting their absorption, binding, distribution, excretion, biotransformation, or drug-drug interactions. Genetic differences in the metabolism of xenobiotics among inbred strains of various laboratory animals and model systems are reviewed. The inbred mouse has been studied most extensively. Genetic differences in toxicity are shown to be caused by various environmental pollutants in several inbred strains of mice and in siblings of the (C57BL/6N)(DBA/2N)F1 X DBA/2N backcross, in which the phenotypes "aromatic hydrocarbon responsiveness" or "nonresponsiveness" had been predetermined. This trait of "responsiveness"--which refers to the capacity for induction of cytochrome P1450 and numerous monooxygenase activities by certain aromatic compounds--segregates almost exclusively as a single gene among offspring of this backcross. All nonresponsive mice ingesting benzo/a/pyrene (about 125 mg/kg per day) die within 4 weeks, whereas the survival of responsive mice receiving the chemical orally is not significantly different from that of control mice; the apparent cause of early death in these experiments in toxic depression of the bone marrow. The life span of animals exposed to certain environmental pollutants can therefore be markedly influenced by a single gene or a very small number of genes. The same genetic trait can be either beneficial or detrimental to the animal, depending on whether detoxification or metabolic potentiation occurs. There also may exist genetic differences in man's susceptibility to toxicity or cancer caused by the numerous foreign compounds in his environment.