Raunio H, Hakkola J, Hukkanen J, Lassila A, Päivärinta K, Pelkonen O, Anttila S, Piipari R, Boobis A, Edwards R J
Department of Pharmacology and Toxicology, University of Oulu, Finland.
Exp Toxicol Pathol. 1999 Jul;51(4-5):412-7. doi: 10.1016/S0940-2993(99)80031-1.
The pattern of expression of individual cytochrome P450 (CYP) forms participating in the metabolism of xenobiotics is being increasingly well characterised in the human pulmonary tissue. Recent studies using methods having increased sensitivity and specificity, such as the reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, have revealed constitutive and inducible expression of several CYP forms in different cell types of the human lung. These studies have revealed the presence of mRNA of several procarcinogen-activating CYP forms in whole lung tissue and alveolar macrophages, including CYP1A1, CYP2B6/7, CYP2E1, and CYP3A5. The results of several studies on CYP2D6 expression have yielded contradictory results. Immunohistochemical analysis shows that CYP3A5 protein is present in all lung samples studied, and is localized in the ciliated and mucous cells of the bronchial wall, bronchial glands, bronchiolar ciliated and terminal cuboidal epithelium, type I and type II alveolar epithelium, vascular and capillary endothelium, and alveolar macrophages. Also CYP3A4 protein is found in some cell types in a minority (about 20%) of lung samples. Primary cultures of freshly isolated broncho-alveolar macrophages as well as a continuously growing bronchial carcinoma cell line (A-549) are being used for CYP induction studies in our laboratory. The results indicate that CYP1 family members are inducible in these cells by polycyclic aromatic hydrocarbon (PAH) inducers, and that CYP3A5, but not CYP3A4, is present constitutively. The results of these studies indicate that several different xenobiotic-metabolizing CYPs are present in the human lung and lung-derived cell lines, possibly contributing to in situ activation of pulmonary procarcinogens. Interindividual differences in the expression of these CYPs may contribute to the risk of developing lung cancer and possibly other pulmonary diseases initiated by agents that require metabolic activation.
参与外源性物质代谢的各个细胞色素P450（CYP）亚型在人肺组织中的表达模式正越来越多地得到明确。最近使用具有更高灵敏度和特异性的方法（如逆转录聚合酶链反应（RT-PCR）分析）进行的研究表明，几种CYP亚型在人肺的不同细胞类型中呈组成性和诱导性表达。这些研究揭示了全肺组织和肺泡巨噬细胞中几种前致癌物激活CYP亚型的mRNA的存在，包括CYP1A1、CYP2B6/7、CYP2E1和CYP3A5。关于CYP2D6表达的几项研究结果相互矛盾。免疫组织化学分析表明，CYP3A5蛋白存在于所有研究的肺样本中，定位于支气管壁的纤毛和黏液细胞、支气管腺、细支气管纤毛和终末立方上皮、I型和II型肺泡上皮、血管和毛细血管内皮以及肺泡巨噬细胞中。在少数（约20%）肺样本的某些细胞类型中也发现了CYP3A4蛋白。我们实验室正在使用新鲜分离的支气管肺泡巨噬细胞的原代培养物以及持续生长的支气管癌细胞系（A-549）进行CYP诱导研究。结果表明，CYP1家族成员可被多环芳烃（PAH）诱导剂在这些细胞中诱导，并且CYP3A5呈组成性存在，而CYP3A4则不然。这些研究结果表明，几种不同的外源性物质代谢CYP存在于人肺和肺源性细胞系中，可能有助于肺前致癌物的原位激活。这些CYP表达的个体差异可能导致患肺癌的风险增加，也可能导致由需要代谢激活的物质引发的其他肺部疾病。
