Genetic susceptibility to toxic substances and its relationship to carcinogenesis.

Although environment is a major factor that determines the incidence of cancer, in some cases heredity plays an important role. Some hereditary conditions cause a particular predisposition that depends upon host activation of chemical carcinogens. The metabolism of many carcinogens is related genetically to the Ah locus and, hypothetically, this gene can control their activation. Some inbred strains of mice and, probably, also some humans seem to possess a natural ability to metabolize chemical carcinogens, and therefore are more susceptible to cancer. The debrisoquine metabolic system, which is defective in 6-8% of the Caucasian population, is probably closely related to the Ah locus, and some relationship to cancer has been reported. N-Acetyl-transferase is known to be involved in acetylation, also, and thus in deactivation of the arylamines that are potent bladder carcinogens. Since the enzyme exhibits a distinct polymorphism, slow acetylation affects the susceptibility to cancer. There are suggestions, also, that the genetically determined phenotype of glucose-6-phosphate dehydrogenase and alpha 1-antitrypsin plays a role in individual susceptibility to cancer.