CYP3A4 VARIBILITY · Identification and characterization of the factors involved in CYP3A4 inter-individual variability
6РП — Действия „Мария Кюри“
- Период
- 2005-06-15 → 2006-06-14
- Финансиране от ЕС
- 40 000 €
- Участници
- 1
- Схема
- ERG
Линиите свързват координатора с партньорите. За проекти отпреди 2014 г. CORDIS не винаги дава точни координати. Тези точки са на ниво град или държава.
Накратко на български
Генетичните разлики в ензима CYP3A4 определят колко бързо тялото преработва лекарства, като например някои хора с конкретен вариант на гена имат по-ниска активност на този ензим. Това помага да се разбере защо ефектът от химиотерапията при определени лимфоми варира.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Final Activity Report Summary - CYP3A4 VARIBILITY (Identification and characterization of the factors involved in CYP3A4 inter-individual variability)
In this project we have investigated genetic factors contributing to cytochrome P450 3A4 (CYP3A4) inter-individual variability. In addition, we have focused on peripheral T-cell lymphomas and shown the relevance of inter-individual differences in CYP3A4 expression, in terms of drug treatment outcome. With respect to the genetic factors contributing to CYP3A4 inter-individual variability, first we showed that CYP3A4 mRNA and hnRNA contents vary in parallel in human liver. This suggests that mechanisms affecting CYP3A4 transcription, such as promoter polymorphisms, could be relevant for inter-individual differences in CYP3A4 expression. Then, we studied the effect of six CYP3A4 single nucleotide polymorphisms (SNPs) on in vivo CYP3A4 activity. One hundred forty three Tanzanian healthy volunteers were phenotyped using quinine as a CYP3A probe and association studies showed that individuals carrying CYP3A4-1B had a significantly lower activity than those with CYP3A4-1. Whereas, no differences were seen for five other SNPs investigated. Functional in vitro studies supported that CYP3A4-1B is a polymorphism with functional importance for inter-individual differences in CYP3A4 expression. With respect to drug treatments, previous data had shown that CYP3A enzymes were differentially expressed in peripheral T-cell lymphoma (PTCL) tumours. Because CYP3A had been shown to influence chemotherapy outcome by inactivation of cytotoxic drugs, we investigated whether CYP3A4 expression in the tumour cells could have an impact on patients' survival. When PTCL survival and CYP3A4 expression was analysed, we found that low survival was associated with high CYP3A4 expression. Kaplan-Meier curves and Cox analysis by quartiles resulted in significant differences of p=0.008 and p=0.02, respectively. Furthermore, the tumours among the fourth quartile of CYP3A4 expression, showed a median survival of 6 months, while the tumours in first quartile had a median survival of 18 months. In conclusion, we have shown that CYP3A4-1B influences CYP3A4 activity and that a high CYP3A4 expression could be associated with a poor outcome of PTCLs chemotherapy.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
The molecular basis that makes a therapeutic drug become toxic has an enormous clinical relevance: it has been estimated that the fatal adverse drug reactions are between the 4th and 6th leading cause of death in developed countries. In addition, the lack of therapeutic effect of a drug by a deficient formation of the active metabolite or by its fast elimination can also lead to death.The cytochrome P450s (CYPs) are the most relevant enzymes catalysing the biotransformation of drugs, and many of the fatal adverse drug reactions, as well as a lack of therapeutic effect of drugs, are due to an abnormal CYP activity. In the human liver the most important enzyme catalysing the biotransformation of drugs is the cytochrome P450 3A4 (CYP3A4).This CYP is involved in the metabolism of 50% of currently used therapeutic drugs. As a consequence, variations in CYP3A4 activity have a major impact on pharmacokinetics and metabolic fate of drugs, drug-drug interactions and toxicology. In the population there are great differences in CYP3A4 activity and the result is a great inter-individual variability in the susceptibility to toxics, optimal drug doses and adverse reactions.Nowadays, CYP3A4 activity variability is unpredictable, since the molecular mechanisms responsible for it are still unknown. Several studies have shown that this variability is genetically determined, ruling out environmental factors. In this project we intend to identify the critical mechanisms regulating CYP3A4 expression and then investigate whether these mechanisms are susceptible of inter-individual variability.In a first step, the obtained information (genetic markers) will be used in connection to cardiovascular diseases, trying to find an association between them and the pharmacological effect obtained with different drugs. Finally, we intent find a simple test, in connection with selected genetic markers, able to predict CYP3A4 activity.
Оригинален текст от CORDIS (на английски).
Участници
- FUNDACIÓN CENTRO NACIONAL DE INVESTIGACIONES ONCOLÓGICAS CARLOS III · MADRIDКоординаторНиво градИспания
Връзки
Данни: CORDIS, © Европейски съюз