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Identification and characterization of the factors involved in CYP3A4 inter-individual variability

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.