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postulated for indirect effects in which acute exposure to a drug infl uences signaling
pathways that may lead to an alteration of transcription factor activity at gene
promoters. This stimulation results in the altered expression of receptors, signaling
molecules, and other proteins necessary to alter genetic regulatory circuits. With
more chronic exposure, cells adapt by an unknown hypothetical process that results
in more permanent modifi cations to DNA methylation and chromatin structure,
leading to enduring alteration of a given epigenetic network. Therefore, any epigen-
etic side-effect caused by a drug may persist after the drug is discontinued. It is
further proposed that some iatrogenic diseases such as tardive dyskinesia and drug-
induced systemic lupus erythematosus are epigenetic in nature. If this hypothesis is
correct the consequences for modern medicine are profound, since it would imply
that our current understanding of pharmacology is an oversimplifi cation. Thus epi-
genetic side-effects of pharmaceuticals may be involved in the etiology of heart
disease, cancer, neurological and cognitive disorders, obesity, diabetes, infertility,
and sexual dysfunction. It is suggested that a systems biology approach employing
microarray analyses of gene expression and methylation patterns can lead to a better
understanding of long-term side-effects of drugs, and that in the future, epigenetic
assays should be incorporated into the safety assessment of all pharmaceutical
drugs. The impact of pharmacoepigenomics may be equal to or greater than that of
pharmacogenetics.
Future Role of Pharmacogenetics in Personalized Medicine
The number of polymorphisms identifi ed in genes encoding drug metabolizing
enzymes, drug transporters, and receptors is rapidly increasing. In many cases,
these genetic factors have a major impact on the pharmacokinetics and pharmaco-
dynamics of a particular drug and thereby infl uence the sensitivity to such drug in
an individual patient with a certain genotype. The highest impact is seen for drugs
with a narrow therapeutic index, with important examples emerging from treatment
with antidepressants, oral anticoagulants, and cytostatics, which are metabolized by
CYP4502D6, CYP2C9, and TPMT, respectively. Many of the genes examined in
early studies were linked to highly penetrant, single-gene traits, but future advances
hinge on the more diffi cult challenge of elucidating multi-gene determinants of drug
response.
In order to apply the increasing amount of pharmacogenetic knowledge to clini-
cal practice, specifi c dosage recommendations based on genotypes will have to be
developed to guide the clinician, and these recommendations will have to be evalu-
ated in prospective clinical studies. Such development will lead to personalized
medicines, which hopefully would be more effi cient and will result in fewer adverse
drug reactions.
4 Pharmacogenetics