Pharmacogenomics.
Pharmacogenomics, a revolutionary chapter in the history of pharmacology, has received new impetus from the development and accessibility of molecular biotechnologies, notably DNA chips. The longstanding notion of responders/non-responders has given way to a more organic approach, where idiosyncrasy becomes an obsolete concept. This is a major step towards predictive, individualized medicine. In this review, several applications of pharmacogenomics are considered. Genetic polymorphisms of metabolization reactions, mainly with cytochrome P450, explain most of the cases described today. More fundamental and innovative studies have tried to link the structure of receptors or transporters and drug response. A leading topic in neuropsychopharmacology is the relation between the polymorphism of dopaminergic receptors and the efficacy of, or adverse reaction to, neuroleptics. In asthma, the structure of the beta2-adrenergic receptor has been associated with response to treatment. Intrinsic genetic predisposition also plays an important role in cardiovascular diseases, and the role of ion channel mutations will be discussed. Research in oncological molecular epidemiology has explored the connection between the predisposition to certain cancers and specific enzymatic equipment hindering the detoxification of potentially carcinogenic exogenous compounds, or, on the contrary, promoting metabolic activation implicated in the formation of reactive compounds. The search for determinants of addictive behavior is another vast field of pharmacogenomics. Finally, we consider the impact of pharmacogenomics on the methodology of drug development in preclinical and clinical trials. Progress in methods of phenotyping/genotyping should promote diagnosis, guide the choice of drug for an individual (benefit/risk ratio), and determine dosage and regimen.
Department of Pharmacology, Medical Faculty, Rennes I University, France.
Olivier
O
Tribut
Yvon
Y
Lessard
Jean-Michael
JM
Reymann
Hervé
H
Allain
Danièle
D
Bentué-Ferrer
D002320:Cardiovascular Physiological Phenomena; D002490:Central Nervous System / Q000502:physiology; D002986:Clinical Trials as Topic; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015195:Drug Design; D005838:Genotype; D006801:Humans; D008780:Methyltransferases / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism; D010597:Pharmacogenetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D012143:Respiratory Physiological Phenomena; D019966:Substance-Related Disorders / Q000503:physiopathology
D003577:Cytochrome P-450 Enzyme System; D008780:Methyltransferases; C022745:thiopurine methyltransferase