Author/Editor     Stocco, Gabriele; Martelossi, Stefano; Decorti, Giuliana; Ventura, Alessando; Malusa, Noelia; Bartoli, Fiora; Giraldi, Tullio
Title     Pharmacogenetics of thiopurines: can posology be guided by laboratory data?
Translated title     Farmakogenetika tiopurinov: ali so laboratorijski podatki lahko odločilni v pozologiji?
Type     članek
Source     Radiol Oncol
Vol. and No.     Letnik 38, št. 2
Publication year     2004
Volume     str. 101-9
Language     eng
Abstract     Background. The purpose of this study was to investigate the relationships between the presence of mutations in the TPMT gene, the consequent reduced enzymatic activity, and the clinical toxicity of the treatment with thiopurine antimetabolite drugs. Materials and methods. The study was performed on 44 patients with inflammatory bowel disease treated with AZA. DNA was extracted from blood samples collected from each patient, and genotyping was performed using specific polymerase chain reaction assays in order to detect the three more frequent mutations of the gene. Enzymatic activity was measured on red blood cell lysates by HPLC. Results. Among the subjects, 4 (9.0%) were heterozygous for mutations in the TPMT gene; no subject was homozygous for mutations in the TPMT gene. A complete concordance between TPMT mutated genotype and reduced enzymatic activity could be determined. The incidence of toxicity in the subjects with a mutated genotype was not different from that observed in the patients with a normal TPMT gene. Conclusion. Genotyping methods provide a simple and reliable DNA-based strategy to identify TPMT homozygotes that should avoid thiopurines administration. However, it seems that the most common, less dangerous forms of thiopurine toxicity could be caused by factors different from TPMT gene mutations examined.
Summary     lzhodišče. Namen študije je bil ugotoviti odvisnost med mutacijami v genu TPMT, oslabljeno encimsko aktivnostjo zaradi teh mutacij in klinično toksičnostjo zdravljenja s tiopurinskimi antimetaboliti. Material in metode. V študijo smo vključili 44 bolnikov z vnetnim obolenjem črevesja, ki so bili zdravljeni z azatioprinom. Iz vzorcev krvi vsakega bolnika smo izločili DNK in določili genotip s polimerazno verižno reakcijo, da bi tako našli tri najpogostejše genske mutacije. Encimsko aktivnost smo merili z visokoločljivostno tekočinsko kromatografijo na razgrajenih celičnih vsebinah rdečih krvničkah. Rezultati. Med izbranimi bolniki so bili 4 (9,0%) pri mutacijah gena TPMT heterozigotni, medtem ko med njimi pri teh mutacijah nihče ni bil homozigoten. Z raziskavo lahko potrdimo popolno soodvisnost med mutiranim genotipom TPMT in oslabljeno encimsko aktivnostjo. Pri primerjanju posameznikov z mutiranim genotipom in normalnim genotipom TPMT nismo opazili sprememb v toksičnosti. Zaključek. Z metodami genotipiziranja, ki temeljijo na strateški uporabnosti DNK, je mogoče enostavno in zanesljivo odkriti homozigote TPMT - posameznike, ki jih ne smemo zdraviti s tiopurini. Hkrati pa ugotavljamo, da običajnejše in manj nevarne oblike toksičnosti tiopurinov povzročajo drugi dejavniki, ki niso povezani z mutacijami omenjenega gena TPMT.
Descriptors     INFLAMMATORY BOWEL DISEASES
6-MERCAPTOPURINE
AZATHIOPRINE
METHYLTRANSFERASES
GENOTYPE
POLYMERASE CHAIN REACTION
CHROMATOGRAPHY, HIGH PRESSURE LIQUID
POLYMORPHISM, RESTRICTION FRAGMENT LENGTH