Related Experiment Video

Updated: Apr 14, 2026

Author Spotlight: Genetic Profiling for Fluorouracil Response in Gastric Cancer
06:21

Author Spotlight: Genetic Profiling for Fluorouracil Response in Gastric Cancer

Published on: May 10, 2024

1.4K

Undetected toxicity risk in pharmacogenetic testing for dihydropyrimidine dehydrogenase

Felicia Stefania Falvella1, Marta Caporale2, Stefania Cheli3

  • 1Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences, University Hospital "Luigi Sacco", Università di Milano, Milan 20157, Italy. falvella.stefania@hsacco.it.

International Journal of Molecular Sciences
|April 24, 2015
PubMed

Insights

Dihydropyrimidine dehydrogenase (DPD) gene variations impact fluoropyrimidine drug safety in colorectal cancer patients. Pharmacogenetic testing for DPYD variants can guide personalized dosing, reducing severe adverse reactions.

Area of Science:

  • Pharmacogenomics
  • Oncology
  • Drug Metabolism

Background:

  • Fluoropyrimidines are standard colorectal cancer treatments but cause severe toxicity in 10-30% of patients.
  • Dihydropyrimidine dehydrogenase (DPD) enzyme activity, crucial for 5-fluorouracil metabolism, is linked to this toxicity.
  • DPYD gene polymorphisms are known to decrease DPD activity, increasing toxicity risk.

Purpose of the Study:

  • To review the role of DPYD genetic variations and epigenetic factors in fluoropyrimidine toxicity.
  • To assess the clinical utility of pharmacogenetic testing for personalized fluoropyrimidine dosing in colorectal cancer.

Main Methods:

  • Literature review of studies investigating DPYD polymorphisms and DPD activity.
  • Analysis of epigenetic regulation of DPD expression, including promoter methylation and microRNAs.
  • Evaluation of pharmacogenetic testing for guiding fluoropyrimidine treatment.

Main Results:

  • Specific non-functional DPYD variants necessitate fluoropyrimidine dose adjustment or avoidance.
  • Conflicting data exist for other common DPYD variants, requiring further validation.
  • DPYD promoter methylation and microRNA regulation may influence DPD activity and toxicity risk.

Conclusions:

  • Pharmacogenetic testing for DPYD variants shows promise for personalized fluoropyrimidine dosing.
  • Further research is needed to fully establish the role of DPD in severe toxicity for colorectal cancer patients.
  • Epigenetic modifications of DPD expression warrant further investigation in relation to drug toxicity.

More Related Videos

Developmental Toxicity Assay Based on Real-Time Monitoring of Fibroblast Growth Factor Signal Disruption in Human Induced Pluripotent Stem Cells05:45

Developmental Toxicity Assay Based on Real-Time Monitoring of Fibroblast Growth Factor Signal Disruption in Human Induced Pluripotent Stem Cells

Published on: October 10, 2025

648
Genotyping Single Nucleotide Polymorphisms in the Mitochondrial Genome by Pyrosequencing07:24

Genotyping Single Nucleotide Polymorphisms in the Mitochondrial Genome by Pyrosequencing

Published on: February 10, 2023

2.1K

Related Concept Videos

Pharmacogenetics of Phase I Enzymes: Cytochrome P450 Isozymes01:28

Pharmacogenetics of Phase I Enzymes: Cytochrome P450 Isozymes

Cytochrome P450 (CYP450) enzymes are a superfamily of heme-containing monooxygenases that play a pivotal role in Phase I drug metabolism by catalyzing oxidation and reduction reactions.These enzymes transform lipophilic xenobiotics into more hydrophilic metabolites, facilitating subsequent Phase II conjugation and eventual excretion. The CYP450 family is classified into families (e.g., CYP1–CYP3) and subfamilies (e.g., CYP2A, CYP2C), based on amino acid sequence homology.CYP450...
228
Drug toxicity: Idiosyncratic Reactions01:16

Drug toxicity: Idiosyncratic Reactions

Idiosyncratic drug reactions represent abnormal chemical responses that vary significantly among individuals, ranging from extreme sensitivity to low doses to insensitivity to high doses. These reactions often occur due to the drug's covalent binding with serum proteins, forming a foreign hapten that triggers an immunotoxicological response. The variability in drug reactions has a strong pharmacogenetic foundation, with genetic differences crucial in how individuals metabolize drugs. For...
197
Pharmacogenetics of Phase II Enzymes: N-acetyltransferase, Thiopurine S-methyltransferase, UDP-glucuronosyltransferase01:27

Pharmacogenetics of Phase II Enzymes: N-acetyltransferase, Thiopurine S-methyltransferase, UDP-glucuronosyltransferase

Phase II biotransformation reactions are essential for detoxifying and eliminating xenobiotics, including many pharmaceutical compounds. These reactions typically involve conjugation, the covalent attachment of polar endogenous groups such as glucuronic acid, sulfate, methyl, or acetyl moieties to functional groups introduced during Phase I metabolism. The resulting conjugates are more water-soluble, enabling efficient renal or biliary excretion.The major classes of Phase II enzymes include...
78
Pharmacogenetics of Drug Metabolism: Overview01:27

Pharmacogenetics of Drug Metabolism: Overview

Genetic polymorphism in drug metabolism is crucial to the inter-individual variability observed in drug responses. Drug metabolism primarily involves the chemical modification of drugs and other xenobiotics to enhance their elimination by increasing their polarity. Two main classes of enzymes mediate this biotransformation process: Phase I enzymes, primarily cytochrome P450s, catalyze oxidation and reduction reactions, while other enzymes, such as esterases, mediate hydrolysis, and Phase II...
151
Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu01:29

Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu

Genetic variations significantly influence drug response through pharmacokinetics, receptor interactions, and biologic milieu modifications. Pharmacokinetic alterations impact drug metabolism and clearance, affecting efficacy and toxicity. Variants in drug-metabolizing enzymes, such as CYP2C9 and CYP2C19, alter drug activation and elimination. For example, CYP2C9 loss-of-function variants require lower warfarin doses to prevent excessive bleeding, while CYP2C19 variants reduce clopidogrel...
127
Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase01:11

Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase

Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
70