Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Int J Environ Res Public Health. 2012 Aug;9(8):2788-800. doi: 10.3390/ijerph9082788. Epub 2012 Aug 3.
Environmental exposure to benzene occurs through cigarette smoke, unleaded gasoline and certain types of plastic. Benzene is converted to hematotoxic metabolites by the hepatic phase-I enzyme CYP2E1, and these metabolites are detoxified by the phase-II enzyme NQO1. The genes encoding these enzymes are highly polymorphic and studies of these polymorphisms have shown different pathogenic and prognostic features in various hematological malignancies. The potential role of different cytochrome p450 metabolizing enzymes in the pathogenesis of acute myeloid leukemia (AML) in an area of active interest. In this study, we demonstrate aberrant CYP2E1 mRNA over-expression by quantitative real-time polymerase chain reaction in 11 cases of de novo AML with inv(16); CBFβ-MYH11. CYP2E1 mRNA levels correlated with CBFβ-MYH11 transcript levels and with bone marrow blast counts in all cases. CYP2E1 over-expression correlated positively with NQO1 mRNA levels (R(2) = 0.934, n = 7). By immunohistochemistry, CYP2E1 protein was more frequently expressed in AML with inv(16) compared with other types of AML (p < 0.001). We obtained serial bone marrow samples from two patients with AML with inv(16) before and after treatment. CYP2E1 mRNA expression levels decreased in parallel with CBFβ-MYH11 transcript levels and blast counts following chemotherapy. In contrast, CYP1A2 transcript levels did not change in either patient. This is the first study to demonstrate concurrent over-expression of CYP2E1 and NQO1 mRNA in AML with inv(16). These findings also suggest that a balance between CYP2E1 and NQO1 may be important in the pathogenesis of AML with inv(16).
环境中的苯暴露可通过香烟烟雾、无铅汽油和某些类型的塑料来实现。苯在肝相 I 酶 CYP2E1 的作用下转化为血液毒性代谢物，这些代谢物由相 II 酶 NQO1 解毒。编码这些酶的基因高度多态性，对这些多态性的研究表明，在各种血液恶性肿瘤中具有不同的发病机制和预后特征。不同细胞色素 p450 代谢酶在急性髓细胞白血病（AML）发病机制中的潜在作用是一个活跃的研究领域。在这项研究中，我们通过定量实时聚合酶链反应（PCR）在 11 例伴有 inv（16）的初发性 AML 患者中证实 CYP2E1mRNA 过表达；CBFβ-MYH11。CYP2E1mRNA 水平与所有病例的 CBFβ-MYH11 转录水平和骨髓原始细胞计数相关。CYP2E1 过表达与 NQO1mRNA 水平呈正相关（R2=0.934，n=7）。通过免疫组织化学，CYP2E1 蛋白在伴有 inv（16）的 AML 中比其他类型的 AML 更频繁地表达（p<0.001）。我们从两名伴有 inv（16）的 AML 患者中获得了治疗前后的连续骨髓样本。CYP2E1mRNA 表达水平与化疗后 CBFβ-MYH11 转录水平和原始细胞计数平行下降。相比之下，两名患者的 CYP1A2 转录水平均未发生变化。这是第一项证明伴有 inv（16）的 AML 中同时过表达 CYP2E1 和 NQO1mRNA 的研究。这些发现还表明，CYP2E1 和 NQO1 之间的平衡可能在伴有 inv（16）的 AML 发病机制中很重要。
