INUBE Extremadura Biosanitary University Research Institute, CICAB Clinical Research Centre, Badajoz University Hospital; University of Extremadura, Badajoz, Spain.
RIBEF Ibero American Network of Pharmacogenetics and Pharmacogenomics, León, Nicaragua.
Pharmacogenomics J. 2021 Apr;21(2):140-151. doi: 10.1038/s41397-020-00190-9. Epub 2020 Oct 6.
Interethnic variability in the drug-metabolizing capacity of CYP450 enzymes may lead to discrepancies in the relationship between genotypes and phenotypes worldwide. The present study was aimed to analyze for the first time whether there is a relationship between clinically relevant CYP450 genetic polymorphisms and their drug oxidation capacity (metabolic phenotype) in a population of healthy Nicaraguan volunteers. Two hundred and twelve participants were genotyped for CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, and their actual metabolic phenotype (evaluated by the Metabolic Ratio, MR) was analyzed by using the CEIBA cocktail approach. The results showed the wide interindividual variability in all the studied enzymes and a significant difference (p < 0.004) in the activity of CYP1A2 between male and female subjects. The number of CYP2C19 (p < 0.0001) and CYP2D6 (p < 0.0001) active alleles were shown inversely correlated with their corresponding MR, although there were marked genotype-phenotype discrepancies. There was an actual enzyme capacity overlapping (MR) between genotypically Poor (gPMs) and Extensive Metabolizers (gEMs) of 3.14% subjects for CYP2D6 and 0.94% for CYP2C9. Similarly, there was an overlapping for metabolic phenotypes of 11.48% of genotypically ultrarapid metabolizers (gUMs) for CYP2C19 and 2.09% for CYP2D6 and gEMs. Therefore, the current approach for metabolic phenotype prediction based just on genotype does not predict properly for all individuals within this Nicaraguan Mestizo population, thus representing a potential barrier for the clinical implementation of personalized medicine in this region. However, it is necessary to improve the prediction of phenotype from genotype in order to improve the pharmacogenetic implementation in populations with specific ethnic backgrounds.
CYP450 酶的药物代谢能力在不同种族间存在差异，这可能导致全球范围内基因型与表型之间的关系存在差异。本研究旨在首次分析在尼加拉瓜健康志愿者人群中，临床相关 CYP450 遗传多态性与药物氧化能力（代谢表型）之间是否存在关联。对 212 名参与者进行 CYP1A2、CYP2C9、CYP2C19、CYP2D6 和 CYP3A4 的基因分型，并使用 CEIBA 鸡尾酒方法分析其实际代谢表型（通过代谢比 MR 评估）。结果表明，所有研究酶的个体间差异很大，且男性和女性 CYP1A2 活性存在显著差异（p<0.004）。CYP2C19（p<0.0001）和 CYP2D6（p<0.0001）的有效等位基因数量与其相应的 MR 呈负相关，尽管存在明显的基因型-表型差异。对于 CYP2D6，基因型Poor 代谢者（gPMs）和广泛代谢者（gEMs）之间的实际酶能力（MR）重叠率为 3.14%，对于 CYP2C9 为 0.94%。同样，对于 CYP2C19 的基因型超快代谢者（gUMs）和 gEMs，代谢表型的重叠率为 11.48%，对于 CYP2D6 为 2.09%。因此，目前基于基因型预测代谢表型的方法并不能正确预测尼加拉瓜梅斯蒂索人群中所有个体，这代表了在该地区实施个体化医学的一个潜在障碍。然而，有必要提高从基因型预测表型的能力，以改善具有特定种族背景的人群中的药物遗传学实施。
