Clinica Chimica Acta

Department Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil.
Clinica Chimica Acta (Impact Factor: 2.82). 08/2008; 398(1-2):15-20. DOI: 10.1016/j.cca.2008.07.032
Source: PubMed


The cytochrome P450 isoenzyme 3A5 (CYP3A5) has an important role on biotransformation of xenobiotics. CYP3A5 SNPs have been associated with variations on enzyme activity that can modify the metabolism of several drugs.
In order to evaluate the influence of CYP3A5 variants on response to lowering-cholesterol drugs, 139 individuals with hypercholesterolemia were selected. After a wash-out period of 4 weeks, individuals were treated with atorvastatin (10 mg/day/4 weeks). Genomic DNA was extracted by a salting-out procedure. CYP3A5*3C, CYP3A5*6 and CYP3A5*1D were analyzed by PCR-RFLP and DNA sequencing.
>Frequencies of the CYP3A5*3C and CYP3A5*1D alleles were lower in individuals of African descent (*3C: 47.8% and *1D: 55.2%) than in non-Africans (*3C: 84.9% and *1D 84.8%, p<0.01). Non-Africans carrying *3A allele (*3C and *1D combined alleles) had lower total and LDL-cholesterol response to atorvastatin than non-*3A allele carriers (p<0.05).
CYP3A5*3A allele is associated with reduced cholesterol-lowering response to atorvastatin in non-African individuals.

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    • "The CYP3A5 gene may be one of the important genetic contributors to inter-individual and inter-racial differences in the response to and clearance of CYP3A-metabolized statins. Willrich et al. (2008) found that the CYP3A5*3A allele was associated with an attenuated cholesterol-lowering response to 10 mg of atorvastatin in 139 non-African individuals. Kim et al. (2007) examined the simvastatin plasma concentration in 22 individuals over 12 h after the ingestion of a single dose of 20 mg and found that the mean area (± SD) under the plasma concentration-time curve for simvastatin in CYP3A5*1/*1 carriers was significantly lower than in CYP3A5*3/*3 carriers and that the mean oral clearance (± SD) was also significantly different between CYP3A5*1/*1 and CYP3A5*3/*3 carriers. "
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    ABSTRACT: In this work, we examined the impact of polymorphism in the cytochrome P450 (CYP) 3A5 gene, CYP3A5*1 (6986A > G, rs 776746), on the reduction in the lipid levels caused by simvastatin and atorvastatin. We studied 350 hyperlipidemic patients who received 10-40 mg of atorvastatin (n = 175) or simvastatin (n = 175) daily. Genotyping for CYP3A5 was done by PCR-RFLP analysis. Differences in the lipid profile before and after treatment were expressed as the % difference. The frequency of CYP3A5 polymorphism was 13.4% for heterozygotes and 86.6% for homozygotes. Comparison of the responses to same dose of each drug showed that the highest % difference was associated with total cholesterol (TC) in subjects receiving atorvastatin 40 mg compared with simvastatin 40 mg (p = 0.048). However, comparison of the responses to equivalent doses of atorvastatin vs. simvastatin revealed no difference in the % change in any of the lipid parameters examined. In individuals with the same CYP3A5 genotype, a head to head comparison of the efficacy of the same dose of simvastatin vs. atorvastatin revealed an advantage for atorvastatin. For equivalent doses of atorvastatin vs. simvastatin there was no difference in the % change in any of the lipid parameters examined. Within the same genotype there was a significant difference in the % change related to the drug treatment.
    Genetics and Molecular Biology 05/2015; 38(2):129-137. DOI:10.1590/S1415-4757382220140239 · 1.20 Impact Factor
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    • "CYP3A5*1D (rs15524) was detected by DNA sequencing. Primer sequences and PCR thermal cycling conditions were previously published [20]. For quality control purposes, 5% of all samples were repeated and genotype accuracy was confirmed by DNA sequencing using the capillary electrophoresis system Mega BACE 1000 (Amersham Pharmacia Biotech, Upsala, Sweden) after PCR amplification using sets of primers designed with Primer Premier® v. 5.0 (Premier Biosoft International, USA). "
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    ABSTRACT: Background: Variability of response to statins has been related to polymorphisms in genes involved in cholesterol homeostasis and statin metabolism, such as CYP3A4 and CYP3A5. We investigated the effects of atorvastatin on CYP3A4 and CYP3A5 mRNA expression in mononuclear cells and on CYP3A activity and their interactions with common variants. Methods: Unrelated individuals (n=121) with hypercholesterolemia (HC) were treated with atorvastatin (10 mg/day/4 weeks). Ninety-two normolipidemic (NL) subjects were selected as a control group. Genotype analysis of CYP3A4*1B (rs2740574), CYP3A4*22 (rs35599367), CYP3A5*3C (rs776746), and CYP3A5*1D (rs15524) and mRNA levels in peripheral blood mononuclear cells (PBMCs) were estimated. CYP3A activity was phenotyped by the urinary cortisol to 6-beta-hydroxy-cortisol ratio. Results: LDL cholesterol reduction in response to atorvastatin was positively correlated with change in CYP3A4 (R(2)=0.039, p=0.037) and CYP3A5 (R(2)=0.047, p=0.019) mRNA levels and negatively correlated with CYP3A activity (R(2)=0.071, p=0.022). CYP3A5*3C (AGT haplotype) was associated to lower basal CYP3A5 mRNA expression in HC (p<0.045), however none of the haplotype groups impacted treatment. Conclusion: It is likely that cholesterolemia status changes promoted by atorvastatin play a role in regulating CYP3A4 and CYP3A5 mRNA expression in PBMCs, as well as CYP3A activity. CYP3A5*3C (AGT haplotype) also contributes for the variability of CYP3A5 mRNA levels in PBMCs.
    Clinica chimica acta; international journal of clinical chemistry 03/2013; 421. DOI:10.1016/j.cca.2013.03.007 · 2.82 Impact Factor
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    • "This is particularly evident in the brown-intermediate group (ACA 0.25–0.50), which presented a high relative contribution of ACA (0.65), an observation previously reported by other studies (Sakuma et al., 2004; Suarez-Kurtz et al., 2007a; Willrich et al., 2008) of Brazilians. The 34-plex AIM-SNPs used provide a simple but effective means to determine the proportion of ACA in our sample population in a statistically secure way. "
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    ABSTRACT: Balancing the subject composition of case and control groups to create homogenous ancestries between each group is essential for medical association studies. We explored the applicability of single-tube 34-plex ancestry informative markers (AIM) single nucleotide polymorphisms (SNPs) to estimate the African Component of Ancestry (ACA) to design a future case-control association study of a Brazilian urban sample. One hundred eighty individuals (107 case group; 73 control group) self-described as white, brown-intermediate or black were selected. The proportions of the relative contribution of a variable number of ancestral population components were similar between case and control groups. Moreover, the case and control groups demonstrated similar distributions for ACA <0.25 and >0.50 categories. Notably a high number of outlier values (23 samples) were observed among individuals with ACA <0.25. These individuals presented a high probability of Native American and East Asian ancestral components; however, no individuals originally giving these self-described ancestries were observed in this study. The strategy proposed for the assessment of ancestry and adjustment of case and control groups for an association study is an important step for the proper construction of the study, particularly when subjects are taken from a complex urban population. This can be achieved using a straight forward multiplexed AIM-SNPs assay of highly discriminatory ancestry markers.
    Genetic Testing and Molecular Biomarkers 01/2012; 16(6):524-30. DOI:10.1089/gtmb.2011.0267 · 1.46 Impact Factor
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