ROLE OF GENETICS AND DRUG-METABOLISM IN HUMAN CANCER RISK

The research field concerning responses to drugs having a hereditary basis is called 'pharmacogenetics'. At least 5 dozen pharmacogenetic polymorphisms have been described in clinical medicine; many are responsible for marked differences in genetic predisposition toward toxicity or cancer. Three are detailed here: the acetylation, the debrisoquine, and the AH locus polymorphism. All 3 are very common among the United States' population: 1 in 2 is a 'slow acetylator', 1 in 12 is a 'poor metabolizer' for more than 2 dozen commonly prescribed drugs in the debrisoquine panel, and the CYP1A1 and CYP1A2 (cytochromes P(1)450 and P(3)450) genes are highly inducible by cigarette smoke in 1 of 10 patients. Differences in xenobiotic metabolism between individuals in the same family can be greater than 200-fold, suggesting that occupationally hazardous chemicals, as well as prescribed drugs having a narrow therapeutic window, might cause strikingly dissimilar effects between patients of differing genotypes. Our ultimate goal is 'preventive toxicology', i.e. the development of simple, inexpensive, unequivocal and sensitive assays to predict individual risk of toxicity or cancer. These tests could help the individual in choosing a safer life style or place of work and might aid the physician in deciding which drug to prescribe.