Genetic basis of toxic reactions to drugs and chemicals

Abstract

Inter-individual drug effects are subject to substantial variability. There are multiple reasons based on pathophysiological factors and environmental interactions, but also genetic characteristics. Groundbreaking successes have been achieved in the field of pharmacogenomics and toxicogenomics. In particular, the identification of hereditary polymorphisms in genes of the cytochrome P450 system and phase II-enzymes such as TMPT contributed considerably to the explanation of the individually varying pharmacokinetics of a number of drugs. Furthermore, hereditary variations in genes of membrane drug transporters were recently discovered. Along with these factors, which could influence pharmacokinetics, strong efforts have been undertaken to clarify the role of genetic polymorphisms in receptors or signal transduction proteins modulating drug efficacy. Particularly for malignant diseases such as bladder or lung cancer, polymorphic foreign compound metabolizing enzymes have been identified as susceptibility factors, modulating an individual's cancer risk dependent on the extent of environmental exposure. This review focuses on the role of the polymorphic phase I enzymes cytochrome P450 1A1, 1A2, 1B1, 2C9, 2C19, 2D6, 3A5 and myeloperoxidase as well as on the phase II-enzymes arylamine N-acetyltransferases 1 and 2, glutathione S-transferases M1 and T1, and thiopurine S-methyltranferases as detoxifying but also toxifying factors, modulating pharmacokinetics and disease susceptibility.