Genetic and environmental factors causing variation in drug response.
Large pharmacokinetic variations, ranging in magnitude from 4- to 40-fold, often exist among the members of a given population. These variations create differences in risk of cancer by accelerating metabolic activation of certain environmental carcinogens in some subjects, while retarding such rates in other subjects. To identify specific genetic and environmental causes of large interindividual variations in these rates, several methods have been developed to probe hepatic cytochrome P-450 isozymes responsible for xenobiotic activation. In patients, dynamic interactions occur between genetic and environmental factors causing large interindividual variations in xenobiotic metabolism. Even the same patient can change dosage requirements with time and condition. Appropriate marker drugs can sensitively indicate pharmacokinetic capacity at any given time in a patient or normal volunteer. With respect to genetic factors, twin and family studies are the traditional methods used to test pharmacogenetic hypotheses. Representative examples are cited to illustrate how twin and family studies serve this purpose. Monogenic control of large interindividual variations in the activity of approx. 12 P-450 isozymes has been described. Individual metabolic pathways need to be investigated for drugs biotransformed by multiple pathways. Since many hepatic P-450 isozymes are extremely sensitive to perturbation by numerous environmental alterations, the critical role of selection criteria is stressed to assure that all subjects of twin and family studies are under as uniform environmental conditions as possible. Otherwise, the operation of genetic factors may be concealed or misinterpreted in studies that do not use gene cloning or protein sequence.
Vesell
E S
ES
Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey 17033.
D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004790:Enzyme Induction; D006801:Humans; D008099:Liver / Q000201:enzymology; D009369:Neoplasms / Q000139:chemically induced; D010375:Pedigree; D010597:Pharmacogenetics; D010599:Pharmacokinetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D012307:Risk Factors; D014427:Twins
D003577:Cytochrome P-450 Enzyme System