Rosemary J, Surendiran A, Rajan S, Shashindran C H, Adithan C
Pharmacogenomics Laboratory, Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, India.
Indian J Med Res. 2006 May;123(5):665-70.
Phenytoin, a widely used anti-epileptic drug, is metabolized mainly by CYP2C9 (90%) and partly by CYP2C19 (10%) to its major metabolite 5-(para-hydroxyphenyl)-5- phenylhydantoin (p-HPPH). The CYP2C9 and CYP2C19 genes encoding these enzymes are polymorphically expressed and most of the variants result in decreased metabolism of the respective substrates. The present study was undertaken to investigate the influence of the CYP2C9*2 and 3 as well as CYP2C192 and *3 variant genotypes on phenytoin hydroxylation in healthy subjects from south India.
A total of 27 healthy, unrelated, subjects were administered a single oral dose of 300 mg phenytoin. Four hours later, 5 ml of blood was collected and genotyped for CYP2C9*1, *2, 3, CYP2C191, *2 and *3 by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Phenytoin and the major metabolite p-HPPH were estimated by reverse phase HPLC. The metabolic ratio was calculated as concentration of phenytoin/p-HPPH.
A significant correlation was observed between the CYP2C9 genotype and metabolic ratio of phenytoin/p-HPPH (r = 0.472, 95% CI 0.100 to 0.728; P = 0.01). While no association was found with CYP2C19 alone, a significant correlation was observed between the combined CYP2C9 and CYP2C19 genotypes and phenytoin metabolic ratio (r = 0.507, 95% CI 0.146 to 0.749; P< 0.01).
CYP2C9*2 and *3 mutant alleles caused decreased hydroxylation of phenytoin in vivo, whereas the mutant alleles of CYP2C19 played only a minor role in the metabolism of phenytoin in subjects of our study. The results of present preliminary study needs to be confirmed with a larger sample.
苯妥英是一种广泛使用的抗癫痫药物，主要通过CYP2C9（90%）代谢，部分通过CYP2C19（10%）代谢为其主要代谢产物5 - （对羟基苯基）-5 - 苯基乙内酰脲（p - HPPH）。编码这些酶的CYP2C9和CYP2C19基因呈多态性表达，大多数变体导致各自底物的代谢减少。本研究旨在调查CYP2C92和3以及CYP2C192和3变体基因型对印度南部健康受试者苯妥英羟基化的影响。
总共27名健康、无亲缘关系的受试者单次口服300 mg苯妥英。4小时后，采集5 ml血液，通过聚合酶链反应 - 限制性片段长度多态性（PCR - RFLP）方法对CYP2C9*1、*2、3、CYP2C191、2和3进行基因分型。通过反相高效液相色谱法测定苯妥英及其主要代谢产物p - HPPH。代谢率计算为苯妥英浓度/p - HPPH浓度。
观察到CYP2C9基因型与苯妥英/p - HPPH的代谢率之间存在显著相关性（r = 0.472，95%可信区间0.100至0.728；P = 0.01）。虽然单独与CYP2C19未发现关联，但观察到CYP2C9和CYP2C19联合基因型与苯妥英代谢率之间存在显著相关性（r = 0.507，95%可信区间0.146至0.749；P < 0.01）。
CYP2C92和3突变等位基因导致体内苯妥英羟基化减少，而在我们研究的受试者中，CYP2C19突变等位基因在苯妥英代谢中仅起次要作用。本初步研究结果需要用更大样本进行证实。
