Kivistö K T, Griese E U, Fritz P, Linder A, Hakkola J, Raunio H, Beaune P, Kroemer H K
Fischer-Bosch-Institut für Klinische Pharmakologie, Stuttgart, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 1996 Jan;353(2):207-12. doi: 10.1007/BF00168759.
We have previously demonstrated expression of cytochrome P 450 3A (CYP3A) protein in pulmonary carcinomas and surrounding normal tissue, using immunohistochemistry. These results suggested that different CYP3A enzymes may be expressed in normal and tumour tissue. Therefore, the aim of the present study was to identify specific CYP3A enzymes expressed in normal human lung and lung tumours. Both normal lung tissue and tumour tissue from eight patients was analyzed for CYP3A4, CYP3A5 and CYP3A7 mRNA using a specific RT-PCR (reverse transcriptase-polymerase chain reaction) method. Identical samples were subjected to immunohistochemical analysis of CYP3A protein. CYP3A5 was the major enzyme of the CYP3A subfamily present at the mRNA level in both normal human lung and lung tumours. CYP3A5 mRNA was detected in normal lung tissue in all eight cases and in tumour tissue in four cases. CYP3A7 mRNA was detected in five cases in normal tissue and in one tumour. Notably, no CYP3A4 mRNA was found in any of the samples. Immunohistochemical staining for CYP3A protein was found in normal lung tissue in each case. Interestingly, all pulmonary carcinomas showed immunostaining for CYP3A, while mRNA for CYP3A enzymes was found in only four cases. In summary, our study indicates a specific expression pattern of the members of the CYP3A subfamily in normal human lung and lung tumours. These findings have potential clinical significance, since it has been recently shown that CYP3A5 catalyzes the activation of the anticancer pro-drugs cyclophosphamide and ifosfamide. Thus, local activation of these agents may take place in pulmonary carcinomas and surrounding normal tissues.
我们之前利用免疫组织化学方法，证实了细胞色素P450 3A（CYP3A）蛋白在肺癌组织及周围正常组织中的表达。这些结果表明，正常组织和肿瘤组织中可能表达不同的CYP3A酶。因此，本研究的目的是鉴定在正常人类肺组织和肺肿瘤中表达的特定CYP3A酶。使用特异性逆转录聚合酶链反应（RT-PCR）方法，对8例患者的正常肺组织和肿瘤组织进行CYP3A4、CYP3A5和CYP3A7 mRNA分析。对相同样本进行CYP3A蛋白的免疫组织化学分析。CYP3A5是CYP3A亚家族在正常人类肺组织和肺肿瘤中mRNA水平上的主要酶。在所有8例正常肺组织样本及4例肿瘤组织样本中均检测到CYP3A5 mRNA。在5例正常组织样本及1例肿瘤样本中检测到CYP3A7 mRNA。值得注意的是，在任何样本中均未发现CYP3A4 mRNA。在每例正常肺组织样本中均发现了CYP3A蛋白的免疫组织化学染色。有趣的是，所有肺癌均显示出CYP3A免疫染色，而仅在4例中发现了CYP3A酶的mRNA。总之，我们的研究表明CYP3A亚家族成员在正常人类肺组织和肺肿瘤中具有特定的表达模式。这些发现具有潜在的临床意义，因为最近研究表明CYP3A5可催化抗癌前体药物环磷酰胺和异环磷酰胺的活化。因此，这些药物可能在肺癌组织及周围正常组织中发生局部活化。
