Prevalence of Cytidine Deaminase and Ribonucleotide Reductase Polymorphism in Thai Healthy Volunteers
Duanggamon Muengsaen¹, Thikhumporn Areesinpitak¹, Kosin Wirasorn², Wichittra Tassaneeyakul¹, Suda Vannaprasaht¹
Affiliation : ¹ Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand ² Oncology Unit, Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
Background: Gemcitabine is a chemotherapy used in many types of solid tumor treatment. It is metabolized to inactive forms by the cytidine deaminase (CDA) enzyme. Gemcitabine inhibits ribonucleotide reductase (RRs) activity, decreasing the nucleotide substrate for DNA replication. Recent data showed that CDA and Ribonucleotide reductase subunit 1 (RRM1) genotypes are associated with gemcitabine efficacy and adverse effects.
Objective: This study investigated the prevalence of CDA and RRM1 polymorphisms in the Thai population and the correlation between CDA polymorphisms and CDA activity.
Materials and Methods: One hundred and forty healthy Northeastern Thai volunteers were enrolled. CDA enzyme activity was evaluated by measuring residual enzyme activity in plasma. The principle of the assay was based on the conversion of cytidine to uridine, which releases ammonium (NH3). The released NH3 was then measured by spectrophotometry. Total proteins in plasma were assayed using the standard Bradford method. CDA and RMM1 genotypes were analyzed using a real-time PCR with specific TaqMan® probes.
Results: The prevalence of CDA*1/*1 and CDA*1/*2 in the Thai healthy volunteers was 80.72% and 19.28%, respectively. CDA*3 allele mutant was not found in the present study. The prevalence of CDA+435C>T consisted of CDA+435C/C 70.54%, CDA+435C/T 26.36% and CDA+435T/T 3.1%. There was no statistical difference in the CDA activity of CDA*2 and CDA+435C>T allele mutants. However, males presented significantly higher CDA activity than females (p=0.027). Moreover, the result showed that the activity was significantly lower in older volunteers (over 50 years old) than in younger volunteers (p=0.047). The prevalence of RRM1-37C>A genotypes were RRM1-37C/C 48.84%, RRM1-37C/A 41.86% and RRM1-37A/A 9.03%. Finally, the prevalence of RRM1-524T>C gene genotype was RRM1-524T/T 49.61%, RRM1-524T/C 37.98%, and RRM1-524C/C 12.4%. The prevalence of CDA*2 and CDA+435T allele frequency was statistically significantly lower than in Caucasian populations (p<0.001). The prevalence of RRM1-524C allele frequency was lower than in Caucasian populations (p<0.003).
Conclusion: CDA activity was not related to CDA genotypes. However, CDA activity was related to age and gender. Allele frequencies of CDA and RRM1 allele mutants in Thais that were different from Caucasian populations may affect the efficacy and toxicity of gemcitabine in Thais.
Received 7 February 2024 | Revised 23 May 2024| Accepted 30 May 2024
DOI: 10.35755/jmedassocthai.2024.S01.S55-S62
Keywords : Gemcitabine; CDA; RRM1; CDA activity; Polymorphism
All Articles
Download