Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
J Pharmacol Exp Ther. 2010 Feb;332(2):599-611. doi: 10.1124/jpet.109.161026. Epub 2009 Oct 23.
The commonly prescribed antiepileptic drug phenytoin has a narrow therapeutic range and wide interindividual variability in clearance explained in part by CYP2C9 and CYP2C19 coding variants. After finding a paradoxically low urinary phenytoin metabolite (S)/(R) ratio in subjects receiving phenytoin maintenance therapy with a CYP2C91/1 and CYP2C191/2 genotype, we hypothesized that CYP2C9 regulatory polymorphisms (rPMs), G-3089A and -2663delTG, in linkage disequilibrium with CYP2C192 were responsible. These rPMs explained as much as 10% of the variation in phenytoin maintenance dose in epileptic patients, but were not correlated with other patients' warfarin dose requirements or with phenytoin metabolite ratio in human liver microsomes. We hypothesized the rPMs affected CYP2C9 induction by phenytoin, a pregnane X receptor (PXR), and constitutive androstane receptor (CAR) activator. Transfection studies showed that CYP2C9 reporters with wild-type versus variant alleles had similar basal activity but significantly greater phenytoin induction by cotransfected PXR, CAR, and Nrf2 and less Yin Yang 1 transcription factor repression. Phenytoin induction of CYP2C9 was greater in human hepatocytes with the CYP2C9 wild type versus variant haplotype. Therefore, CYP2C9 rPMs affect phenytoin-dependent induction of CYP2C9 and phenytoin metabolism in humans, with an effect size comparable with that for CYP2C92 and 2C9*3. These findings may also be relevant to the clinical use of other PXR, CAR, and Nrf2 activators.
常用的抗癫痫药物苯妥英的治疗范围狭窄，清除率个体间差异很大，部分原因是 CYP2C9 和 CYP2C19 编码变异。在发现接受苯妥英维持治疗的 CYP2C91/1 和 CYP2C191/2 基因型的受试者的尿苯妥英代谢物（S）/（R）比值异常低后，我们假设 CYP2C9 调节多态性（rPMs），G-3089A 和-2663delTG，与 CYP2C192 连锁不平衡，是造成这种情况的原因。这些 rPMs 可以解释多达 10%的癫痫患者苯妥英维持剂量的变异，但与其他患者的华法林剂量需求或人肝微粒体中苯妥英代谢物比值无关。我们假设 rPMs 影响苯妥英诱导的 CYP2C9，苯并二恶烷 X 受体（PXR）和组成型雄烷受体（CAR）激活剂。转染研究表明，与野生型等位基因相比，具有变异等位基因的 CYP2C9 报告基因具有相似的基础活性，但与共转染的 PXR、CAR 和 Nrf2 相比，苯妥英诱导作用更大，而 Yin Yang 1 转录因子抑制作用更小。与 CYP2C9 变异型相比，具有 CYP2C9 野生型的人肝细胞中苯妥英诱导 CYP2C9 的作用更大。因此，CYP2C9 rPMs 影响人类中依赖苯妥英的 CYP2C9 诱导和苯妥英代谢，其作用大小与 CYP2C92 和 2C9*3 相当。这些发现可能与其他 PXR、CAR 和 Nrf2 激活剂的临床应用也有关。
