Low levels of oxygen (hypoxia) have been reported in solid tumours. This hypoxic microenvironment modulates the expression of genes linked to a more aggressive disease. However, it is unclear if the expression of drug-metabolizing enzymes as cytochromes P450 (CYPs) is affected by hypoxia in cancer. We aimed to define which cytochromes are affected by hypoxia using a liver cancer model in vitro. For this purpose, we assessed whole-genome expression microarrays of HepG2 liver cancer cell line from free repository databases, looking for gene expression hypoxia-associated profiles and selected those cytochromes with significant differences. Then, we corroborated their mRNA expression and protein levels by RT-qPCR and western blot, respectively, as well as immunofluorescence. Based on microarray analysis, we found that the expression of CYP2S1 and CYP24A1 were up-regulated with at least twice fold change compared with normoxia. The levels of mRNA and protein of CYP2S1 and CYP24A1 were increased significantly in hypoxic conditions (P < .05), and this tendency was also observed by immunofluorescence assays. Our data show that the expression of cytochromes CYP2S1 and CYP24A1 are induced in hypoxia, being the first time that CYP24A1 expression is associated with tumour hypoxia; which might have consequences in cancer progression and drug resistance.

中文翻译：

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缺氧作为细胞色素 P450 的调节剂：细胞色素 CYP2S1 和 CYP24A1 在缺氧条件下在人肝癌细胞中的过度表达

据报道，实体瘤中存在低水平的氧气（缺氧）。这种缺氧微环境调节与更具侵袭性的疾病相关的基因的表达。然而，尚不清楚药物代谢酶作为细胞色素 P450 (CYPs) 的表达是否受到癌症缺氧的影响。我们旨在使用体外肝癌模型来确定哪些细胞色素受缺氧影响。为此，我们评估了来自免费存储库数据库的 HepG2 肝癌细胞系的全基因组表达微阵列，寻找与缺氧相关的基因表达谱，并选择了那些具有显着差异的细胞色素。然后，我们分别通过 RT-qPCR 和蛋白质印迹以及免疫荧光证实了它们的 mRNA 表达和蛋白质水平。基于微阵列分析，我们发现与常氧相比，CYP2S1 和 CYP24A1 的表达上调至少两倍。CYP2S1和CYP24A1的mRNA和蛋白水平在缺氧条件下显着升高（P  < .05)，免疫荧光分析也观察到了这种趋势。我们的数据显示细胞色素CYP2S1和CYP24A1在缺氧条件下表达，首次发现CYP24A1表达与肿瘤缺氧有关；这可能会对癌症进展和耐药性产生影响。