Pharmacoepigenetics is an emerging field that studies the underlying epigenetic marking patterns that lead to variation in an individual's response to medical treatment.
[1] Due to genetic heterogeneity, environmental factors, and pathophysiological causes, individuals that exhibit similar disease expression may respond differently to identical drug treatments.
Now, an increasing amount of evidence shows that epigenetics also plays an important role in determining the safety and efficacy of drug treatment in patients.
Besides being drug targets, epigenetic changes are also used as diagnostic and prognostic indicators to predict disease risk and progression, and this could be beneficial for the improvement of personalized medicine.
Now, pharmacoepigenetics has an additional focus: the development of therapeutic epidrugs that can make changes to the epigenome in order to lessen the cause or symptoms of a disease in an individual.
Even though a large gap still remains between the knowledge of epigenetic modifications on drug metabolism mechanisms and clinical applications, pharmacoepigenetics has become a rapidly growing field that has the potential to play an important role in personalized medicine.
In particular, scientists have extensively studied the associations of DNA methylation, histone modifications, regulatory microRNA with the development of diseases.
Additionally, microRNA is a type of noncoding RNA that is responsible for altering gene expression by targeting and marking mRNA transcripts for degradation.
[7][8] One of the main effects of drug exposure early in life is altered ADME (Absorption, Distribution, Metabolism, and Excretion) gene expression.
[9][8] A new emerging field, closely related to pharmacoepigenetics, is toxicoepigenetics that captures toxicological epigenetic changes as a result of the exposure to different compounds (drugs, food, and environment).
Cyp2e1 mediated hydroxylation of its probe drug chlorzoxazone to its metabolite, 6-hydroxychlorzoxazone, correlated negatively with DNA methylation and positively with histone acetylation in mouse microsome extracts.
[13] A study in prostate cancer demonstrated that the protein's regulatory region was under the control of the histone modification H3K4me3, which typically indicates active gene expression in non-cancerous cells.
[1] This abnormal methylation typically causes histone modification and changes in chromatin structure at a local level, thus effecting gene expression.
[7] DNA methyltransferase inhibitors are being pursued due to the hypermethylation of tumor suppressor genes and increased DNMTs that have been observed in cancer cells.
Introduction of these inhibitors can result in reduced promoter methylation and expression of previously silenced tumor suppressor genes.
[18] Some examples include procaine, hydralazine, and procainimide, but they lack specificity and potency making it hard to test them in clinical trials.
While the mechanism is still under investigation, it is believed that adding the HDAC inhibitors results in increased histone acetylation and therefore the reactivation of transcription of tumor suppressor genes.
There are around 14 different HDAC inhibitors being investigated in clinical trials for haematological and solid tumors, but more research needs to be done on the specificity and mechanisms by which they are inhibiting.
For example, with SWI/SNF loss of function mutations, DNA replication and repair is negatively affected and can give rise to tumors if cell growth goes unchecked.
[17] Frequently observed in lung cancer is the methylation of gene promoters that are involved in critical functions like cell-cycle control, repairing DNA, cell adhesion, proliferation, apoptosis, and motility.
[20] The hypertrophic changes that occur in cardiac muscles cells result from the required acetylation of histone tails via acetyltransferases.
[19] There are an increasing number of scientific publications that are finding that miRNA plays a key role in various aspects of heart failure.
Antagomirs are single strand RNAs that are complementary, which have been chemically engineered oligonucleotides that silence miRNAs so that they cannot degrade the mRNA that is needed for normal levels of expression.
To increase gene expression, one may try to decrease CpG methylation by using a drug that works as DNA methyltransferase inhibitor such as decitabine or 5-aza-2'-deoxycytidine.
Sodium butyrate is another chemical that inhibits class I HDACs, thus resulting in the ability for transcription factors to easily access and express the gene.
While laboratory results indicate relationships between genes and potential drug interactions that could mitigate the effects of mutations, the complexity of the human genome and epigenome makes it difficult to develop therapies that are safe, efficient, and consistent.
Proteins containing bromodomains recognize and bind acetylated lysine residues in histones, causing chromatin structure modification and a subsequent shift in levels of gene expression.
[18] Using a BET inhibitor can reduce the over expression of bromodomain proteins, which can cause aberrant chromatin remodeling, transcription regulation, and histone acetylation.
[25] Additionally, studies have demonstrated that HDACi are useful in minimizing damage after a stroke, and encouraging angiogenesis and myogenesis in embryonic cells.
Repression of this methyltransferase action at targeted loci can prevent recurring transfer of methyl groups to these sites and keep them open to transcriptional machinery, allowing more tumor-suppression genes to be made.