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Pharmacogenetics of deoxycytidine kinase: identification and characterization of novel genetic variants

Jatinder K Lamba1, Kristine Crews, Stanley Pounds

  • 1Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 332 North Lauderdale St., Memphis, TN 38105, USA. jatinder.lamba@stjude.org

The Journal of Pharmacology and Experimental Therapeutics
|September 15, 2007
PubMed

Insights

Genetic variations in deoxycytidine kinase (DCK) affect its activity and expression, impacting nucleoside analog metabolism. These DCK genetic changes may predict patient response to therapies like cytarabine (ara-C).

Area of Science:

  • Pharmacogenomics
  • Enzyme kinetics
  • Molecular biology

Background:

  • Deoxycytidine kinase (DCK) is crucial for activating nucleoside analog drugs, including cytarabine (ara-C).
  • Genetic variations in DCK can influence drug efficacy and toxicity.
  • Understanding DCK genetic variants is essential for personalized cancer therapy.

Purpose of the Study:

  • To identify and characterize genetic variants in the deoxycytidine kinase (DCK) gene.
  • To determine the functional impact of identified DCK variants on enzyme activity and expression.
  • To explore the association between DCK genetic variations and intracellular drug metabolite levels.

Main Methods:

  • Sequencing of the DCK promoter and coding exons in European (CEPH) and African (YRI) ancestry panels.
  • In vitro characterization of recombinant DCK variants to assess enzyme activity (Km, Vmax).
  • Analysis of DCK mRNA expression and association with single-nucleotide polymorphisms (SNPs) in patient cohorts.

Main Results:

  • Sixty-four genetic polymorphisms were identified in DCK, including three nonsynonymous variants (I24V, A119G, P122S) that reduced enzyme activity.
  • DCK variants exhibited altered kinetic parameters (Km, Vmax) and lower activity in lymphoblast cell lines.
  • Ethnic differences in DCK mRNA expression were observed, with higher levels in African ancestry subjects.
  • A 3'-untranslated region SNP (35708 C>T) was associated with lower DCK mRNA expression and lower ara-CTP levels in acute myeloid leukemia patients.

Conclusions:

  • Genetic variations in DCK significantly influence its enzymatic activity and gene expression.
  • These findings highlight the role of DCK genetic polymorphisms in inter-individual variability of nucleoside analog metabolism.
  • DCK genetic profiling may serve as a predictive biomarker for therapeutic response to drugs like cytarabine (ara-C).

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