Study of CYP3A5 gene expression and polymorphisms in hypercholesterolemic individuals treated with atorvastatin
The cytochrome P450 isoenzyme 3A5 (CYP3A5) has an important role on biotransformation of endogenous compounds and xenobiotics. Single nucleotide polymorphisms (SNPs) of the CYP3A5 gene have been associated with variations on gene expression and enzyme activity that can modify the metabolism of several drugs. In order to evaluate the influence of CYP3A5 SNPs on RNAm expression and response to atorvastatin, 99 mormolipidemic (NL) and 139 hypercholesterolemic (HC) individuals have been enrolled in this study. HC patients were treated with atorvastatin (10 mg/day/four weeks). Blood samples were collected before and after treatment for serum lipids analyses, genomic DNA and total RNA extraction. CYP3A5*3C, and CYP3A5*6 SNPs were analyzed by PCR-RFLP. CYP3A5*1D was analyzed by direct sequencing. CYP3A5 RNAm expression in peripheral blood mononuclear cells (PBMC) was evaluated by Real Time PCR. In HC group, the frequencies of CYP3A5*3C and CYP3A5*1D alleles were higher in white individuals (*3C: 84.9% and *1D 84.8%) that in blacks (*3C: 47.8% and *1D: 55.2%, p<0.01). CYP3A5*3C and *1D alleles were in linkage desequilibrium. CYP3A5*6 allelle frequency was higher in blacks (6.8%) that in white individuals (0.6%, p=0.002). There was no association between CYP3A5 SNPs and baseline lipid profile in NL and HC groups. White HC carriers of CYP3A5*3A/*3A haplotype (*3C and *1D combined alleles) have lower total cholesterol and LDL-c response to atorvastatin than non-CYP3A5*3A/*3A carriers (p<0.05). CYP3A5 RNAm expression on PBMC increased in response to atorvastatin (p<0.05) only in CYP3A5*3A/*3A haplotype carriers. These results are suggestive that CYP3A5*3C and CYP3A5*1D SNPs are associated with CYP3A5 gene expression and cholesterol-lowering response to atorvastatin.
Advisor:Rosario Dominguez Crespo Hirata; Rosário Dominguez Crespo Hirata; Edna Regina Nakandakare; Elvira Maria Guerra Shinohara
School:Universidade de São Paulo
Source Type:Master's Thesis
Keywords:Atorvastatin CYP3A5 Farmacogenética Gene expression Hypercholesterolemia Pharmacogenetics
Date of Publication:12/11/2006