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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 transcriptasepolymerase 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 bronchoalveolar 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 situactivation 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.

Expression of the Ah receptor-regulated cytochrome P4501B1 (CYP1B1) gene was studied in human adult and fetal tissues and cells in culture by reverse transcriptase-coupled polymerase chain reaction (RT-PCR). In adults, CYP1B1 mRNA was detected in liver, lymphocytes, cells of bronchoalveolar lavage samples and uterine endometrium, but not in lung. The level of expression was very low in adult liver and only three out of six fetal livers expressed CYP1B1. Extrahepatic fetal tissues, especially brains and kidneys, expressed high levels of CYP1B1. CYP1B1 mRNA was constitutively detected at a low level in first trimester and full-term placental samples. A competitive RT-PCR assay was developed to assess the regulation of CYP1B1. CYP1B1 mRNA was not induced in placenta by maternal cigarette smoking. Inducibility of CYP1B1 in cells in culture by the Ah receptor ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin was studied in primary fibroblasts and chorion carcinoma cell line JEG-3 having different CYP1A1 induction properties. Inducibility of CYP1B1 was found to be regulated independently from CYP1A1. In JEG-3 cells CYP1A1 mRNA was induced up to 9000-fold, while the expression of CYP1B1 was not affected. Expression of Ah receptor and Ah receptor nuclear translocator (regulators of the CYP1 family) was determined in human placenta and in the JEG-3 cell line. Expression of these transcription factors was found neither to be co-regulated nor affected by Ah receptor ligands. This study provides evidence that in addition to the Ah receptor complex, other cell-specific factors modulate the response of CYP1B1 and CYP1A1 to Ah receptor ligands.