Title:Fluoropyrimidine Toxicity: the Hidden Secrets of DPYD
Volume: 25
Issue: 2
Author(s): Vangelis G. Manolopoulos and Georgia Ragia*
Affiliation:
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Dragana Campus, Alexandroupolis, 68100,
Greece
- Individualised Medicine & Pharmacological Research Solutions (IMPReS) Center, Dragana Campus Alexandroupolis,
68100, Greece
Keywords:
Dihydropyrimidine dehydrogenase, DPYD, fluoropyrimidines, 5-FU, capecitabine, toxicity, genetics, epigenetics.
Abstract:
Background: Fluoropyrimidine-induced toxicity is a main limitation of therapy. Currently, polymorphisms
in the DPYD gene, which encodes the 5-FU activation enzyme dihydropyrimidine dehydrogenase
(DPD), are used to adjust the dosage and prevent toxicity. Despite the predictive value of DPYD genotyping, a
great proportion of fluoropyrimidine toxicity cannot be solely explained by DPYD variations.
Objective: We herein summarize additional sources of DPD enzyme activity variability, spanning from epigenetic
regulation of DPYD expression, factors potentially inducing protein modifications, as well as drug-enzyme
interactions that contribute to fluoropyrimidine toxicity.
Results: While seminal in vitro studies provided evidence that DPYD promoter methylation downregulates
DPD expression, the association of DPYD methylation with fluoropyrimidine toxicity was not replicated in
clinical studies. Different non-coding RNA molecules, such as microRNA, piwi-RNAs, circular-RNAs and
long non-coding RNAs, are involved in post-transcriptional DPYD regulation. DPD protein modifications and
environmental factors affecting enzyme activity may also add a proportion to the pooled variability of DPD enzyme
activity. Lastly, DPD-drug interactions are common in therapeutics, with the most well-characterized
paradigm the withdrawal of sorivudine due to fluoropyrimidine toxicity deaths in 5-FU treated cancer patients;
a mechanism involving DPD severe inhibition.
Conclusions: DPYD polymorphisms are the main source of DPD variability. A study on DPYD epigenetics
(both transcriptionally and post-transcriptionally) holds promise to provide insights into molecular pathways
of fluoropyrimidine toxicity. Additional post-translational DPD modifications, as well as DPD inhibition by
other drugs, may explain a proportion of enzyme activity variability. Therefore, there is still a lot we can learn
about the DPYD/DPD fluoropyrimidine-induced toxicity machinery.
