Expression of xenobiotic-metabolizing CYPs in human pulmonary tissue

The pattern of expression of individual cytochrome P450 (CYP) forms partici pating in the metabolism of xenobiotics is being increasingly well characte rised in the human pulmonary tissue. Recent studies using methods having in creased sensitivity and specificity, such as the reverse transcriptase poly merase chain reaction (RT-PCR) analysis, have revealed constitutive and ind ucible expression of several CYP forms in different cell types of the human lung. These studies have revealed the presence of mRNA of several procarci nogen-activating CYP forms in whole lung tissue and alveolar macrophages, i ncluding CYP1A1,CYP2B6/7, CYP2E1,and CYP3A5. The results of several studies on CYP2D6 expression have yielded contradictory results. Immunohistochemic al analysis shows that CYP3A5 protein is present in all lung samples studie d, and is localized in the ciliated and mucous cells of the bronchial wall, bronchial glands, bronchiolar ciliated and terminal cuboidal epithelium, t ype I and type II alveolar epithelium, vascular and capillary endothelium, and alveolar macrophages. Also CYP3A4 protein is found in some cell types i n a minority (about 20 %) of lung samples. Primary cultures of freshly isol ated broncho-alveolar macrophages as well as a continuously growing bronchi al 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 st udies indicate that several different xenobiotic-metabolizing CYPs are pres ent in the human lung and lung-derived cell lines, possibly contributing to in situ activation of pulmonary procarcinogens. Interindividual difference s 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.