Dufour Carlo, Svahn Johanna, Bacigalupo Andrea, Longoni Daniela, Varotto Stefania, Iori Anna Paola, Bagnasco Francesca, Locasciulli Anna, Menna Giuseppe, Ramenghi Ugo, Lanciotti Marina
Hematology Unit, Department of Pediatric Hemato-Oncology, Giannina Gaslini Children's Hospital, Genoa, Italy.
Haematologica. 2005 Aug;90(8):1027-31.
Various drugs and xenobiotics are involved in the pathogenesis of acquired aplastic anemia. Their harmful potential depends on the amount of exposure to them and on the detoxifying capacity of the recipient. Genetic polymorphisms of some important detoxifying enzymes are associated with low or absent cata-lytic activity of the protein. We assessed whether, in a Caucasian population, low or null activity polymorphisms of CYP3A4, GSTT1, GSTM1, GSTP1 and NQO1 were associated with the risk of developing aplastic anemia and with the response to immunosuppressive therapy.
In 77 Caucasian patients with aplastic anemia and in 156 normal controls we evaluated the distribution of the following polymorphisms which are associated with low or no activity of the corresponding enzyme: (i)-290 A-->G of the CYP3A4 gene, deletions of (ii) GSTT1 and (iii) GSTM1 genes, (iv) 313A-->G of the GSTP1 gene and (v) 609 C-->T of the NQO1 gene.
The distribution of the genotypes of all tested polymorphisms was not different in patients and controls. No differences were seen among the patients when the group was subdivided by age and severity of the disease. Only the GSTM1 null genotype was significantly more frequent in male patients than in male controls. The frequency of all tested polymorphisms did not differ in patients who did or did not respond to immunosuppressive therapy.
The low/null activity polymorphisms of the detoxifying enzymes CYP3A4, GSTT1, GSTM1, GSTP1 and NQO1 are not associated with the risk of developing aplastic anemia or to the response to immunosuppressive therapy in Caucasian patients.
多种药物和外源性物质参与获得性再生障碍性贫血的发病机制。它们的有害潜能取决于接触量以及受体的解毒能力。一些重要解毒酶的基因多态性与蛋白质的低催化活性或无催化活性相关。我们评估了在高加索人群中，细胞色素P450 3A4（CYP3A4）、谷胱甘肽S-转移酶T1（GSTT1）、谷胱甘肽S-转移酶M1（GSTM1）、谷胱甘肽S-转移酶P1（GSTP1）和醌氧化还原酶1（NQO1）的低活性或无活性多态性是否与再生障碍性贫血的发病风险以及免疫抑制治疗反应相关。
我们评估了77例高加索再生障碍性贫血患者和156例正常对照中以下与相应酶低活性或无活性相关的多态性分布：（i）CYP3A4基因的-290A→G；（ii）GSTT1基因缺失；（iii）GSTM1基因缺失；（iv）GSTP1基因的313A→G；（v）NQO1基因的609C→T。
所有检测多态性的基因型分布在患者和对照中无差异。按年龄和疾病严重程度对患者进行亚组分析时，各亚组间也无差异。仅GSTM1无效基因型在男性患者中显著高于男性对照。所有检测多态性的频率在免疫抑制治疗有反应和无反应的患者中无差异。
解毒酶CYP3A4、GSTT1、GSTM1、GSTP1和NQO1的低活性/无活性多态性与高加索患者再生障碍性贫血的发病风险或免疫抑制治疗反应无关。
