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

BMC Medical Genetics

Roberta D’Arrigo⁴  Leopoldo Paolo Pucillo⁴  Carlo Federico Perno²  Andrea Antinori¹  Massimo Tempestilli⁴  Caterina Gori³  Mauro Zaccarelli¹  Giulia Berno³ 

[1] Clinical Department, National Institute for Infectious Diseases “L. Spallanzani”, Rome, Italy;Unit of Molecular Virology, Tor Vergata University Hospital, Rome, Italy;Antiviral Drug Monitoring Unit, National Institute for Infectious Diseases “L. Spallanzani”, Rome, Italy;Clinical Biochemistry and Pharmacology Laboratory, National Institute for Infectious Diseases “L. Spallanzani”, Via Portuense 292, Rome, 00149, Italy

关键词: Cytocrome P450;    Pharmacogenetics;    Variability;    Polymorphisms;   

Others  :  848351
DOI  :  10.1186/1471-2350-15-76

 received in 2014-03-24, accepted in 2014-06-25,  发布年份 2014

【 摘 要 】

Background

Drug metabolism via the cytochrome P450 (CYP450) system has emerged as an important determinant in the occurrence of several drug interactions (adverse drug reactions, reduced pharmacological effect, drug toxicities). In particular, CYP3A4 and CYP3A5 (interacting with more than 60% of licensed drugs) exhibit the most individual variations of gene expression, mostly caused by single nucleotide polymorphisms (SNPs) within the regulatory region of the CYP3A4 and CYP3A5 genes which might affect the level of enzyme production.

In this study, we sought to improve the performance of sensitive screening for CYP3A polymorphism detection in twenty HIV-1 infected patients undergoing lopinavir/ritonavir (LPV/r) monotherapy.

Methods

The study was performed by an effective, easy and inexpensive home-made Polymerase Chain Reaction Direct Sequencing approach for analyzing CYP3A4 and CYP3A5 genes which can detect both reported and unreported genetic variants potentially associated with altered or decreased functions of CYP3A4 and CYP3A5 proteins. Proportions and tests of association were used.

Results

Among the genetic variants considered, CYP3A4*1B (expression of altered function) was only found in 3 patients (15%) and CYP3A5*3 (expression of splicing defect) in 3 other patients (15%). CYP3A5*3 did not appear to be associated with decreased efficacy of LPV/r in any patient, since none of the patients carrying this variant showed virological rebound during LPV/r treatment or low levels of TDM. In contrast, low-level virological rebound was observed in one patient and a low TDM level was found in another; both were carrying CYP3A4*1B.

Conclusions

Our method exhibited an overall efficiency of 100% (DNA amplification and sequencing in our group of patients). This may contribute to producing innovative results for better understanding the inter-genotypic variability in gene coding for CYP3A, and investigating SNPs as biological markers of individual response to drugs requiring metabolism via the cytochrome P450 system.

【 授权许可】

   
2014 Berno et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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