THE Ah LOCUS. GENETIC DIFFERENCES IN TOXIC AND TUMORIGENIC RESPONSE TO FOREIGN COMPOUNDS

Abstract

The Ah locus represents a complex “cluster” of genes controlling the induction of numerous drug-metabolizing enzyme “activities” by polycyclic aromatic compounds. The major regulatory gene product is a cytosolic receptor similar in many ways to the steroid receptors. Structural gene products include two (and probably many more) distinctly different forms of cytochrome P 1 -450. Allelic differences at the Ah locus have been shown to be associated in the mouse with increased individual risk for cancer, mutation, DNA binding of reactive metabolites, drug toxicity, birth defects, and enhanced detoxification. These differences presumably reflect increases or decreases in the steady-state level of reactive intermediates in target tissues–because of quantitative increases in P 1 -450 and/or qualitative changes in the metabolite profile generated by newly induced P 1 -450. The genetically “responsive” individual who is at increased risk for cancer caused by subcutaneous or topical or intratracheal polycyclic hydrocarbons is at decreased risk for toxicity of the bone marrow and leukemia caused by oral benzo[a]pyrene, (when compared with the genetically “nonresponsive” individual receiving the same dose of the same xenobiotic). In other words, tissue sites in direct contact with the carcinogen develop cancer in responsive animals because of induced P 1 -450; tissues in distant sites of the body may develop malignancy in nonresponsive animals because more carcinogen reaches that tissue due to decreased P 1 -450 induction all over the body and therefore decreased detoxification. Not only the dose but the route of administration is therefore very important in the interpretation of data from tumorigenesis or toxicity experiments involving P 1 -450 inducers such as polycyclic hydrocarbons.