Genotype and allele frequencies of polymorphic UGT1A9 in the Polish population
- 279 Downloads
The human UDP-glucuronosyltransferase 1A9 (UGT1A9) plays a central role in the metabolism of different therapeutic drugs, carcinogens and endobiotics. The UGT1A9 gene shows genetic polymorphism with frequencies significantly different in populations and ethnic groups. Many of these genetic variants are directly responsible for polymorphic drug metabolism. Three crucial alleles of UGT1A9, UGT1A9*3 (p.Met33Thr), *4 (p.Tyr242X), *5 (p.Asp256Asn) are associated with decrease or absence of enzyme activity, which intensify the risk of toxic effect during biotransformation. The goal of the present study was to discover frequencies of these genetic variations in 308 healthy individuals representing Polish population. The genotypes were determined by pyrosequencing. We demonstrated that the frequency of the variant UGT1A9*3 was 0.016, which suggests the need for detailed analysis of its effect on important drugs metabolism level in Polish population. Alleles UGT1A9*4 and UGT1A9*5 were not present in any of the subjects. So far, no studies have been conducted in which the distribution of these alleles has been determined in the Polish population.
KeywordsUDP-glucuronosyltransferase UGT1A9 Polymorphic drug metabolism Polish population Allele frequencies
This study was supported by grant from the Ministry of Science and Higher Education in Poland (grant number: N401 037 838), European Regional Development Fund—ERDF, European Fund for Innovative Economy and Foundation for Polish Science.
- Girard H, Court MH, Bernard O, Fortier LC, Villeneuve L, Hao Q, Greenblatt DJ, von Moltke LL, Perussed L, Guillemette C (2004) Identification of common polymorphisms in the promoter of the UGT1A9 gene: evidence that UGT1A9 protein and activity levels are strongly genetically controlled in the liver. Pharmacogenetics 14(8):501–515PubMedCrossRefGoogle Scholar
- Girard H, Villeneuve L, Court MH, Fortier LC, Caron P, Hao Q, von Moltke LL, Greenblatt DJ, Guillemette C (2006) The novel UGT1A9 intronic I399 polymorphism appears as a predictor of 7-ethyl-10-hydroxycamptothecin glucuronidation levels in the liver. Drug Metab Dispos 34(7):1220–1228PubMedCrossRefGoogle Scholar
- Jinno H, Saeki M, Saito Y, Tanaka-Kagawa T, Hanioka N, Sai K, Kaniwa N, Ando M, Shirao K, Minami H, Ohtsu A, Yoshida T, Saijo N, Ozawa S, Sawada J (2003) Functional characterization of human UDP-glucuronosyltransferase 1A9 variant, D256N, found in Japanese cancer patients. J Pharmacol Exp Ther 306(2):688–693PubMedCrossRefGoogle Scholar
- Lévesque E, Delage R, Benoit-Biancamano MO, Caron P, Bernard O, Couture F, Guillemette C (2007) The impact of UGT1A8, UGT1A9, and UGT2B7 genetic polymorphisms on the pharmacokinetic profile of mycophenolic acid after a single oral dose in healthy volunteers. Clin Pharmacol Ther 81(3):392–400PubMedCrossRefGoogle Scholar
- Thibaudeau J, Lépine J, Tojcic J, Duguay Y, Pelletier G, Plante M, Brisson J, Têtu B, Jacob S, Perusse L, Bélanger A, Guillemette C (2006) Characterization of common UGT1A8, UGT1A9, and UGT2B7 variants with different capacities to inactivate mutagenic 4-hydroxylated metabolites of estradiol and estrone. Cancer Res 66(1):125–133PubMedCrossRefGoogle Scholar
- Villeneuve L, Girard H, Fortier LC, Gagné JF, Guillemette C (2003) Novel functional polymorphisms in the UGT1A7 and UGT1A9 glucuronidating enzymes in Caucasian and African-American subjects and their impact on the metabolism of 7-ethyl-10-hydroxycamptothecin and flavopiridol anticancer drugs. J Pharmacol Exp Ther 307(1):117–128PubMedCrossRefGoogle Scholar