Pharmacogenomics Laboratory, Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry 605006, India.
Drug Metab Pharmacokinet. 2009;24(6):537-48. doi: 10.2133/dmpk.24.537.
CYP2C19 is a polymorphic enzyme which metabolizes several clinically important drugs including proguanil. Variation in the 5' regulatory region may influence CYP2C19 activity. This study evaluates the relationship between proguanil metabolic ratio and genetic variations of CYP2C19 in a South Indian population. Fifty unrelated healthy subjects were genotyped for CYP2C19 ()2 and ()3 alleles and the 5' flanking region of CYP2C19 was sequenced. Plasma concentrations of proguanil and cycloguanil were estimated by reverse phase HPLC after single oral doses (200 mg) of proguanil. In silico docking analysis of transcription factors binding to its sites in CYP2C19 5' regulatory region was performed. The mean metabolic ratios (proguanil/cycloguanil) were highest in ()1/()2 or ()1/()3 subjects and in ()2/()2 or ()2/()3 as compared to ()1/()1 subjects. Subjects with promoter region variation -98T>C showed decrease in the metabolic ratios irrespective of other variation, which may explain the deviation from the genotype-phenotype association of CYP2C19. In silico analysis predicted alteration in the interaction of transcription factors to their binding sites in the presence of variant alleles. The results of this study would be useful in predicting interindividual differences in the metabolism of substrates of CYP2C19.
CYP2C19 是一种多态酶，可代谢包括普罗喹胺在内的几种重要临床药物。5' 调控区的变异可能影响 CYP2C19 的活性。本研究评估了 CYP2C19 基因 ()2 和 ()3 等位基因和 CYP2C19 5' 侧翼区的遗传变异与印度南部人群中普罗喹胺代谢比之间的关系。50 名无关健康受试者的 CYP2C19 ()2 和 ()3 等位基因进行基因分型，并对 CYP2C19 5' 调控区进行测序。给予普罗喹胺单剂量（200mg）后，通过反相高效液相色谱法测定普罗喹胺和环丙胍的血浆浓度。对其 5' 调控区转录因子结合位点进行计算机模拟对接分析。（）1/()2 或（）1/()3 受试者和（）2/()2 或（）2/()3 受试者的平均代谢比值（普罗喹胺/环丙胍）高于（）1/()1 受试者。启动子区域变异-98T>C 的受试者无论其他变异如何，代谢比值均降低，这可能解释了 CYP2C19 基因型-表型关联的偏差。计算机模拟分析预测，在存在变异等位基因的情况下，转录因子与其结合位点的相互作用会发生改变。本研究的结果将有助于预测 CYP2C19 底物代谢的个体间差异。
