Comparison of genetic variation in drug ADME-related genes in Thais with Caucasian, African and Asian HapMap populations

Abstract

The objectives of this study are to investigate allele frequencies of drug absorption, distribution, metabolism and elimination (ADME)-related genes in the Thai population and to compare these genes to HapMap populations including Caucasians (CEU), Africans (YRI) and Asians (CHB/JPT). Genetic variations of drug ADME-related genes in 190 Thais were investigated using drug metabolizing enzymes and transporters (DMET) plus genotyping system. We examined 1936 single nucleotide polymorphisms (SNPs) of 225 genes that have documented functional and clinical significances in phase I and phase II drug metabolism enzymes, drug transporters and other genes involved in ADME processes. Distributions of genotyping data from Thai were compared with other HapMap populations including Caucasian, African and Asian populations. The analysis demonstrated 43 SNPs with statistical significance comparing among five populations. However, only 26 SNPs showed statistical significance in pair-wise comparisons between Thai versus CEU and Thai versus CHB/JPT. These 26 SNPs belong to 13 groups of drug ADME-related genes which are CYP2A6, CYP3A5, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, VKORC1, COMT, NAT2, TPMT, UGT1A1 and SLCO1B1. These genes demonstrated clinical significances as previously observed in many studies. The results could explain clinical variability in pharmacokinetics and pharmacodynamics of drugs in Thais based on genetic variations in drug ADME-related gene emphasized in this article.

The Metabolization Profile of the CYP2D6 Gene in Amerindian Populations: A Review

“…The principal ancestral human populations-Europeans, Asians, Amerindians, and Africans-present considerable genetic diversity, which implies major fluctuations in the frequencies of important pharmacogenetic polymorphisms [54]. The traditional populations of the Americas have a long history of geographical isolation, and a differentiated genetic makeup in comparison with populations from other regions of the world [24].…”

“…The traditional populations of the Americas have a long history of geographical isolation, and a differentiated genetic makeup in comparison with populations from other regions of the world [24]. The common origin of Native Americans and their autochthonous biological and cultural evolution combine to make the New World an excellent model for studies of the co-evolution between genes and cultures [54]. The papers selected for the present review permitted the compilation of the CYP2D6 gene metabolization profiles of the Amerindian populations of a number of different countries in the Americas.…”

Single Nucleotide Recognition Using a Probes-On-Carrier DNA Chip

“…Genes related to drug absorption, distribution, metabolism and elimination (ADME) are polymorphic, causing the efficacy and toxicity of drugs to vary among individuals [1,2]. Accordingly, assessment of genetic variation, including SNPs, is prerequisite for achieving the best drug response and highest safety margins, thereby improving patient care as a component of personalized medicine.…”

Frequência de polimorfismos nos genes responsáveis pela absorção, distribuição, metabolismo e excreção (ADME) de medicamentos na população brasileira

“…Estas reações resultam na introdução de novos grupos polares (oxidação), na modificação de grupos funcionais existentes (redução) ou no desmascaramento de grupos funcionais polares existentes (hidrólise). Muitas vezes, o produto do metabolismo de fármacos da fase I não será suficientemente polar para ser excretado, assim deve sofrer um metabolismo adicional por enzimas adicionais de fase I ou fase II (12) . A figura 1 mostra a proporção de enzimas que contribuem para o metabolismo de Fase I.…”

“…As enzimas de fase II são responsáveis pelas reações de conjugação, com várias substituições hidrofílicas para formar metabólitos solúveis em água (12,33) . A nova porção química é geralmente ativada por uma coenzima, em seguida, transferida para um grupo funcional, tipicamente álcoois, aminas, ácidos carboxílicos e tióis, na própria droga original ou a outra introduzida no produto do metabolismo da fase I. Os metabólitos resultantes são mais solúveis em água e, portanto, mais fáceis de excretar e/ou têm atividade reduzida.…”