Kidd R S, Curry T B, Gallagher S, Edeki T, Blaisdell J, Goldstein J A
Department of Biopharmaceutical Sciences, Bernard J. Dunn School of Pharmacy, Shenandoah University, Winchester, VA 22601, USA.
Pharmacogenetics. 2001 Dec;11(9):803-8. doi: 10.1097/00008571-200112000-00008.
Cytochrome P450 (CYP) 2C9 is the principal enzyme responsible for the metabolism of numerous clinically important drugs. Two polymorphic alleles CYP2C92 and CYP2C93 have been documented which affect the metabolism and clinical toxicity of drugs such as phenytoin, warfarin, glipizide, and tolbutamide. The present study reports the first example of a null polymorphism in CYP2C9. This mutation dramatically affects the half-life and clinical toxicity of phenytoin. The study subject was a female African-American presented to the emergency department with phenytoin toxicity evidenced by mental confusion, slurred speech, memory loss and the inability to stand. She exhibited extremely poor clearance of phenytoin with an elimination half-life of approximately 13 days. Genotyping studies demonstrated that the patient did not possess any known variant CYP2C9 alleles. Phenytoin is metabolized to a minor extent by the polymorphic CYP2C19, but this individual did not possess any variant CYP2C19 alleles. Sequencing studies revealed that the individual was homozygous for a new CYP2C9 allele (CYP2C9*6) with the deletion of an adenine at base pair 818 of the cDNA. The clearance of phenytoin in this individual is estimated to be approximately 17% of that observed in normal patients. The frequency of this allele was 0.6% (95% confidence limits of 0.1 to 3.5%) in 79 African-Americans and 0% (95% confidence limits of 0 to 1.1%) in 172 Caucasians. The study also demonstrates the severe clinical consequences to patients with a null mutation in CYP2C9 after treatment with normal doses of phenytoin.
细胞色素P450（CYP）2C9是负责多种临床重要药物代谢的主要酶。已记录到两个多态性等位基因CYP2C92和CYP2C93，它们会影响苯妥英、华法林、格列吡嗪和甲苯磺丁脲等药物的代谢及临床毒性。本研究报告了CYP2C9中无效多态性的首个实例。该突变极大地影响了苯妥英的半衰期和临床毒性。研究对象是一名非洲裔美国女性，因精神错乱、言语不清、记忆力丧失和无法站立而被送往急诊科，表现出苯妥英中毒症状。她对苯妥英的清除率极低，消除半衰期约为13天。基因分型研究表明，该患者不拥有任何已知的CYP2C9变异等位基因。苯妥英在一定程度上由多态性的CYP2C19代谢，但该个体不拥有任何CYP2C19变异等位基因。测序研究显示，该个体为一种新的CYP2C9等位基因（CYP2C9*6）的纯合子，其cDNA的第818个碱基对处缺失了一个腺嘌呤。该个体中苯妥英的清除率估计约为正常患者的17%。在79名非洲裔美国人中，该等位基因的频率为0.6%（95%置信区间为0.1%至3.5%），在172名白种人中为0%（95%置信区间为0至1.1%）。该研究还证明了CYP2C9发生无效突变的患者在接受正常剂量苯妥英治疗后会产生严重的临床后果。
