Macé K, Bowman E D, Vautravers P, Shields P G, Harris C C, Pfeifer A M
Nestlé Research Centre, Department of Life Sciences, Lausanne, Switzerland.
Eur J Cancer. 1998 May;34(6):914-20. doi: 10.1016/s0959-8049(98)00034-3.
The human respiratory epithelium is in direct contact with chemical carcinogens and toxins in inhaled air. Therefore, the activities of xenobiotic-metabolising enzymes in this epithelium could modulate respiratory toxicity and carcinogenesis. We determined the expression of several xenobiotic-metabolising enzymes, including phase I and phase II enzymes, in human bronchial mucosa and peripheral lung tissues. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of phase I enzymes showed CYP1A1 and CYP2C (CYP2C8 and CYP2C18) mRNA expression in all of the 14 bronchial mucosa specimens. CYP2A6 and CYP2B6 mRNAs were found in 85% of the samples, whereas 50 and 90% of the tissues displayed CYP2E1 and CYP3A5 expression, respectively. However, CYP1A2, CYP2D6 and CYP3A4 mRNAs were not detected in all samples analysed. Normal human bronchial epithelial cells (NHBE cells) cultured in serum-free conditions showed reduced P450 expression in comparison with the bronchial mucosal samples. Similar to the bronchial mucosa, the peripheral lung tissues expressed CYP1A1, CYP2A6, CYP2B6, CYP2C (CYP2C8 and CYP2C18), CYP2E1 and CYP3A5 mRNAs, but did not show detectable levels of CYP2D6. Additional P450s, such as CYP1A2 and CYP3A4, were detected. The expression of CYP1A1, CYP1A2, CYP2B6, CYP2E1 and CYP3A4/5 in peripheral lung tissues was confirmed at the protein level, whereas CYP2A6 protein was undetectable. The use of specific primers for the detection of the phase II isoenzymes belonging to the glutathione S-transferase mu (GST mu) and N-acetyl transferase (NAT) families showed that GSTM1 was expressed in 40% of the bronchial mucosa and 25% of the peripheral lung tissues, whereas GSTM3 and NAT1 mRNAs were found in all bronchial and lung samples. Finally, NAT2 expression was detected in all peripheral lung tissues, but was not detected in the bronchus. In conclusion, these results describing the diversity of the xenobiotic-metabolising enzymes expressed in the bronchus and lung tissues indicate that the human respiratory system could significantly and specifically contribute to the activation and metabolism of several environmental procarcinogens.
人类呼吸道上皮直接接触吸入空气中的化学致癌物和毒素。因此，该上皮中异源物代谢酶的活性可能会调节呼吸道毒性和致癌作用。我们测定了几种异源物代谢酶在人支气管黏膜和外周肺组织中的表达，包括Ⅰ相和Ⅱ相酶。对Ⅰ相酶的逆转录-聚合酶链反应（RT-PCR）分析显示，在所有14份支气管黏膜标本中均有CYP1A1和CYP2C（CYP2C8和CYP2C18）mRNA表达。85%的样本中发现有CYP2A6和CYP2B6 mRNA，而分别有50%和90%的组织显示有CYP2E1和CYP3A5表达。然而，在所有分析样本中均未检测到CYP1A2、CYP2D6和CYP3A4 mRNA。与支气管黏膜样本相比，在无血清条件下培养的正常人支气管上皮细胞（NHBE细胞）中P450表达降低。与支气管黏膜相似，外周肺组织表达CYP1A1、CYP2A6、CYP2B6、CYP2C（CYP2C8和CYP2C18）、CYP2E1和CYP3A5 mRNA，但未检测到可检测水平的CYP2D6。还检测到了其他P450，如CYP1A2和CYP3A4。外周肺组织中CYP1A1、CYP1A2、CYP2B6、CYP2E1和CYP3A4/5的表达在蛋白水平得到证实，而未检测到CYP2A6蛋白。使用特异性引物检测属于谷胱甘肽S-转移酶μ（GSTμ）和N-乙酰转移酶（NAT）家族的Ⅱ相同工酶显示，40% 的支气管黏膜和25% 的外周肺组织中有GSTM1表达，而在所有支气管和肺样本中均发现有GSTM3和NAT1 mRNA。最后，在所有外周肺组织中检测到NAT2表达，但在支气管中未检测到。总之，这些描述支气管和肺组织中表达的异源物代谢酶多样性的结果表明，人类呼吸系统可能对几种环境前致癌物的激活和代谢有显著且特异性的作用。
