Marsh J C, Chowdry J, Parry-Jones N, Ellis S W, Muir K R, Gordon-Smith E C, Tucker G T
Department of Haematology, St George's Hospital Medical School, London.
Br J Haematol. 1999 Feb;104(2):266-70. doi: 10.1046/j.1365-2141.1999.01190.x.
A genetic susceptibility to drug or chemical toxicity may provide a basis for an increased risk of idiosyncratic aplastic anaemia (AA). The cytochrome P450 enzymes are responsible for the metabolism of many drugs, some of which have been linked to AA. Mutations in the cytochrome P450 CYP2D6 gene result in absent or impaired enzyme activity in about 7% of Caucasians, whereas a specific mutation in the 5'-regulatory region of the CYP2E1 gene causes overexpression of the gene. We evaluated the frequency of allelic variants of CYP2D6 and CYP2E1 using allele-specific PCR amplification and restriction enzyme analysis of blood mononuclear cell DNA among 54 Caucasian AA patients. CYP2D6 and CYP2E1 were chosen because of the link between AA and the antipsychotic drug remoxipride (CYP2D6 substrate) and benzene (CYP2E1 substrate), respectively. Results were compared with 53 controls matched for age, sex and ethnicity. The percentage of AA patients homozygous for the CYP2D63, CYP2D64 alleles (poor metabolizer phenotype) and the CYP2E1 mutant allele (overexpression) was 0%, 4% and 0%, respectively, and the percentage of heterozygotes was 2%, 28% and 15%, respectively. For normal controls the corresponding results for homozygous mutants were 0%, 4% and 0% and for heterozygotes 4%, 25% and 6%, respectively. We concluded that there were no major differences in the frequencies of the genetic polymorphisms between this series of AA patients and controls, but due to the low number of cases with the poor metabolizer phenotype and those with a history of drug exposure, the power of the study was too low to disprove an interaction.
对药物或化学物质毒性的遗传易感性可能是导致特发性再生障碍性贫血（AA）风险增加的一个基础。细胞色素P450酶负责许多药物的代谢，其中一些药物与AA有关。细胞色素P450 CYP2D6基因的突变导致约7%的高加索人酶活性缺失或受损，而CYP2E1基因5'-调控区的一个特定突变会导致该基因过度表达。我们使用等位基因特异性PCR扩增和血液单核细胞DNA的限制性酶切分析，评估了54例高加索AA患者中CYP2D6和CYP2E1等位基因变体的频率。选择CYP2D6和CYP2E1是因为AA分别与抗精神病药物瑞莫必利（CYP2D6底物）和苯（CYP2E1底物）之间存在关联。将结果与53名年龄、性别和种族相匹配的对照进行比较。AA患者中CYP2D63、CYP2D64等位基因（代谢不良者表型）和CYP2E1突变等位基因（过度表达）的纯合子百分比分别为0%、4%和0%，杂合子百分比分别为2%、28%和15%。对于正常对照，纯合突变体的相应结果分别为0%、4%和0%，杂合子分别为4%、25%和6%。我们得出结论，这一系列AA患者和对照之间的基因多态性频率没有重大差异，但由于代谢不良者表型和有药物暴露史的病例数量较少，该研究的效力太低，无法排除相互作用。
