CLINICS 2011;66(6):1041-1044 CLINICAL SCIENCE DOI:10.1590/S1807-59322011000600020 Frequency of genetic polymorphisms of PXR gene in the Brazilian population Ricardo P. P. Moreira,I Alexander A. L. Jorge,II Berenice B. Mendonca,I Taˆ nia A. S. S. BachegaI I Unidade de Endocrinologia do Desenvolvimento, Laborato´ rio de Hormoˆ nios e Gen e´tica Molecular LIM 42, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de S a˜o Paulo, Sa˜ o Paulo, Brazil. II Unidade de Endocrinologia Gene´ tica LIM 25, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de S a˜o Paulo, S a˜o Paulo, Brazil. INTRODUCTION: PXR polymorphisms have been implicated in modulating CYP3A4 and PXR expression, potentially accounting for interindividual differences in drug metabolism. The prevalence of PXR polymorphisms varies among ethnic groups and data on the allelic distribution in the highly mixed Brazilian population is lacking. The aim of this study was to analyze genetic variations in the PXR gene in Brazilians and to compare the results to other ethnic groups. METHODS: DNA samples from 117 healthy Brazilians underwent PCR amplification and sequencing. RESULTS: Eleven polymorphisms were identified, 3 of which are highly associated with differences in CYP3A4 expression. We also identified 1 new synonymous variant in 1.3% of the alleles. Among the functional polymorphisms, –25913 C.T and –6994T.C occurred at a higher frequency compared to the African alleles (p , 0.05) but at a lower frequency compared to Caucasian alleles. The 8055 C.T allele was found at a similar frequency to those described in Caucasians and Africans (p . 0.05). CONCLUSION: We observed that functional variants of the PXR were frequent in our sample of the Brazilian population. Our results suggest that PXR gene variants may be of interest in pharmacogenetic studies involving Brazilians. KEYWORDS: Pharmacogenetics; Allelic distribution; Brazilian population; Genetic variation. Moreira RPP, Jorge AAL, Mendonca BB, Bachega TASS. Frequency of genetic polymorphisms of PXR gene in the Brazilian population. Clinics. 2011;66(6):1041-1044. Received for publication on February 25, 2011; First review completed on March 16, 2011; Accepted for publication on March 16, 2011 E-mail: tbachega@usp.br Tel.: 55 11 30697512 INTRODUCTION The interindividual variability in human drug metabo- lism may be genetically determined by allelic variance in genes encoding P450 proteins and nuclear receptors.1-4 Cytochrome P450s metabolize approximately 80% of clinical drugs and polymorphisms in the CYP3A4 gene have been previously investigated due to its involvement in the metabolism of more than 50% of drugs. Despite the large interindividual differences in CYP3A4 expression, poly- morphisms that impair enzyme activity seem to be rare.5-7 CYP3A4 expression is mainly induced by the pregnane X receptor (PXR),8-10 a member of the orphan nuclear receptor subfamily and the main transcriptional regulator of cyto- chrome P4503A enzymes.8,9 The activation of PXR initiates in the cytoplasm. After exposure to ligands, PXR dimerizes with the retinoic acid receptor (RXR) and binds to nuclear receptor response elements in the upstream regulatory Copyright 2011 CLINICS – This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non- commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. regions of target genes. These genes encode drug-metabo- lizing enzymes such as CYP3A4 and drug transporters,11 which are the main regulators in the uptake and transfor- mation of many prescribed medicines. Several PXR (also known as NR1I2) polymorphisms have been identified that influence the level of PXR expression and, therefore, indirectly regulate its target genes.4,12 These poly- morphisms account for the wide variability of CYP3A4 levels in the population.4,13 The functional effects of these polymorph- isms include aberrant DNA binding and alterations in the transactivation and expression of downstream target genes.4,12 While the allelic distribution of the PXR gene varies widely among different ethnic groups,13-17 it has yet to be studied in the highly mixed Brazilian population. Here we analyze the frequency of PXR variants in a sample of healthy Brazilian subjects. We also compare the frequencies of PXR polymorphisms to those described in Asians, Caucasians, and Africans in order to determine whether PXR variants should be evaluated in pharmacogenetic studies involving Brazilian subjects. Subjects The study protocol was approved by the Ethical Committee of Sa˜o Paulo University. Written consent was 1041