Analysis of single-nucleotide polymorphisms (SNPs) in human CYP3A4 and CYP3A5 genes: potential implications for the metabolism of HIV drugs

摘要

Background: Drug metabolism via the cytochrome P450 (CYP450) system has emerged as an importantuddeterminant in the occurrence of several drug interactions (adverse drug reactions, reduced pharmacological effect,uddrug toxicities). In particular, CYP3A4 and CYP3A5 (interacting with more than 60% of licensed drugs) exhibit theudmost individual variations of gene expression, mostly caused by single nucleotide polymorphisms (SNPs) within theudregulatory region of the CYP3A4 and CYP3A5 genes which might affect the level of enzyme production.udIn this study, we sought to improve the performance of sensitive screening for CYP3A polymorphism detection inudtwenty HIV-1 infected patients undergoing lopinavir/ritonavir (LPV/r) monotherapy.udMethods: The study was performed by an effective, easy and inexpensive home-made Polymerase Chain ReactionudDirect Sequencing approach for analyzing CYP3A4 and CYP3A5 genes which can detect both reported and unreportedudgenetic variants potentially associated with altered or decreased functions of CYP3A4 and CYP3A5 proteins. Proportionsudand tests of association were used.udResults: Among the genetic variants considered, CYP3A4*1B (expression of altered function) was only found in 3udpatients (15%) and CYP3A5*3 (expression of splicing defect) in 3 other patients (15%). CYP3A5*3 did not appear toudbe associated with decreased efficacy of LPV/r in any patient, since none of the patients carrying this variant showedudvirological rebound during LPV/r treatment or low levels of TDM. In contrast, low-level virological rebound wasudobserved in one patient and a low TDM level was found in another; both were carrying CYP3A4*1B.udConclusions: Our method exhibited an overall efficiency of 100% (DNA amplification and sequencing in our group ofudpatients). This may contribute to producing innovative results for better understanding the inter-genotypic variabilityudin gene coding for CYP3A, and investigating SNPs as biological markers of individual response to drugs requiringudmetabolism via the cytochrome P450 system.