Pharmacogenetics and human cancer.
Pharmacogenetics involves research into the hereditary basis for the different responses of different individuals to drugs or other environmental pollutants. Circumstantial evidence from a growing number of laboratory animal model systems suggests that human susceptibility to environmentally caused cancers may be influenced by an underlying genetic predisposition for metabolism of drugs and other foreign chemicals. The Ah locus is an example of a well-characterized model system for studying pharmacogenetics in mice. This complex controls the induction by polycyclic aromatic compounds of numerous drug-metabolizing enzyme 'activities'. 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 detoxication. These differences appear to reflect changes in the steady-state level of reactive intermediates in target tissues. Tissue sites in direct contact with the carcinogen develop cancer more readily in responsive animals because of the presence of induced P1-450; tissues at distant sites of the body may develop malignancy more readily in nonresponsive animals because more carcinogen reaches that tissue, due to decreased P1-450 induction in proximal tissues and, therefore, a decrease in detoxication. Hence, not only the dose but the route of administration, the timing of the dosage, and the site of the tumour or toxicity--relative to the site of administered drug--are all very important in the interpretation of data from carcinogenicity or toxicity experiments involving P1-450 inducers, such as polycyclic hydrocarbons. These data emphasize the utility of studies in intact animals, in which differences in pharmacokinetics and enzyme induction may occur among various tissues; such subtleties cannot be detected in short-term testing with bacteria or tissue cultures. There is sufficient evidence that heritable variation of the Ah complex occurs in man. With the advent of recombinant DNA technology, this laboratory has recently cloned the P1-450 gene. In addition to a better understanding of P-450 induction and evolution of P-450 genes, we hope to develop a more sensitive assay for assessing the human Ah phenotype.
D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004274:DNA, Recombinant; D004790:Enzyme Induction; D005786:Gene Expression Regulation; D006801:Humans; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010088:Oxidoreductases / Q000235:genetics*; D011110:Polymorphism, Genetic; D011955:Receptors, Drug / Q000378:metabolism
D002273:Carcinogens; D004274:DNA, Recombinant; D011955:Receptors, Drug; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D001189:Aryl Hydrocarbon Hydroxylases