Pharmacogenomics of drugs affecting the cardiovascular system.
The variability in drug response originates partly from genetics, with possible consequences for drug efficacy, adverse effects, and toxicity. Until now, pharmacogenetics mainly indicated the best known source of variability, that is, the variability caused by drug metabolism. However, simultaneous progress in the knowledge of biochemical targets of drugs and of the human genome, together with the development of new technologies, revealed many new sources of human genetic variation, e.g., in receptors or transporters. Drugs are metabolized by various polymorphic phase I enzymes, including cytochromes P450 (CYP). Among them, the most relevant for the metabolism of cardiovascular drugs are CYP3A4, CYP2C9 or CYP2C19, and CYP2D6. The role of phase II enzymes is limited with regard to cardiovascular drugs biotransformation, but some polymorphisms (glutathion-S-transferase; GSH-T) are linked to cardiovascular risk. Phase III proteins or transporters, especially from the ABC family, must also be considered, as their polymorphisms affect cholesterol and other sterols transport. Among pharmacological targets, some proteins were identified as involved in interindividual variations in the response to cardiovascular drugs. Some examples are apolipoprotein E, angiotensin-converting enzyme, and the beta-adrenergic receptor. From the risk concept emphasizing impaired metabolism and adverse effects, we now moved to an approach, which is a personalized, genotype-dependent adaptation of therapy.
INSERM U 525, Centre du Médicament, Faculté de Pharmacie, Université Henri Poincaré Nancy I, Nancy, France. gerard.siest@pharma.uhp-nancy.fr
Gérard
G
Siest
Luc
L
Ferrari
Marie-José
MJ
Accaoui
Anne-Marie
AM
Batt
Sophie
S
Visvikis
D002317:Cardiovascular Agents / Q000627:therapeutic use; D002319:Cardiovascular System / Q000187:drug effects*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005838:Genotype; D006801:Humans; D050356:Lipid Metabolism; D009154:Mutation; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic / Q000235:genetics
D002317:Cardiovascular Agents; D003577:Cytochrome P-450 Enzyme System