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The epigenetic basis of drug response

Inter-individual differences in reaction to drugs and pharmacological treatments can cause adverse drug reactions. Understanding the genetic/epigenetic basis of this observation will improve drug design and testing.
The epigenetic basis of drug response
The liver constitutes the primary organ for the metabolism of drugs and xenobiotic substances. The differential response to drugs among individuals can not only limit efficacy but also cause drug-induced liver injury. Genetic polymorphisms in genes encoding enzymes involved in drug metabolism can partly explain the variability in responses to pharmacological treatment. Recent evidence suggests that epigenetic modifications such as DNA hydroxymethylation influence liver function and development.

The EU-funded INTERDRUG (Epigenetic mechanisms underlying inter-individual differences in drug response and hepatic disease) project analysed the genetic basis of these inter-individual differences and developed tools for studying epigenetic contributors.

Sequencing data from more than 6 500 individuals demonstrated great variability in phase I and phase II enzymes as well as drug transporters. These findings underscored the shortcomings of current pharmacogenetic tests and highlighted the need to include these rare genetic variants in drug screening tests.

For epigenetic analysis, the consortium developed an assay capable of resolving both 5-hydroxymethylcytosine and 5-methylcytosine profiles. Their results suggested that the control of hepatic genes relied on both gene- and site-specific epigenetic variability and that previous analysis methods do not accurately reflect hepatic epigenetic profiles.

As a more sensitive model for pharmaceutical and toxicological applications, scientists employed primary human hepatocytes. However, their rapid dedifferentiation in culture significantly limited their use in long-term functional studies. Proteomic and transcriptomic analysis indicated that the downregulation of hepatic genes was due to changes in non-coding RNAs, including miRNAs that could be delayed using small molecule inhibitors. To avoid hepatocyte dedifferentiation, researchers developed a three-dimensional hepatic model system that retained hepatocyte function for over five weeks.

Collectively, the findings of the INTERDRUG study provided a deeper understanding of the mechanisms underlying hepatic gene regulation. Furthermore, the researchers developed novel technologies that permit physiologically relevant studies of liver function and improve the prediction of drug toxicity thus facilitating a wider dissemination of personalized medicine.

Related information

Keywords

Drug, liver, epigenetic modifications, INTERDRUG, hepatocyte
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