EXPRESSION AND LOCALIZATION OF CYP3A4 AND CYP3A5 IN HUMAN LUNG

Expression in the lung of procarcinogen metabolizing P450 enzymes in t he CYP3A subfamily may contribute to the initiation of pulmonary carci nogenesis by agents that require metabolic activation, such as tobacco -derived polycyclic aromatic hydrocarbons. Expression and localization of CYP3A4 and CYP3A5 proteins in human lung were determined by immuno histochemistry with three antibodies, one specific for members of the CYP3A subfamily and two antipeptide antibodies specific for CYP3A4 and CYP3A5, respectively. Positive immunostaining in one or several cell types of the lung was observed in all patients with anti-CYP3A4 and an ti-CYP3A5 antibodies. With the anti-CYP3A4 antibody epithelial stainin g was observed in five cases and staining of alveolar macrophages in 1 2 of 27 cases. To determine which CYP3A genes are transcribed in lung tissue, analysis by reverse-transcriptase-polymerase chain reaction wi th gene-specific primers for CYP3A4, CYP3A5, and CYP3A7 was performed. CYP3A5 mRNA was detected in all eight samples studied, CYP3A4 mRNA in one sample, and CYP3A7 mRNA in none of the samples. CYP3A5 was locali zed by immunohistochemistry in the ciliated and mucous cells of the br onchial wall, bronchial glands, bronchiolar columnar and terminal cubo idal epithelium, type I and type II alveolar epithelium, vascular and capillary endothelium, and alveolar macrophages, whereas CYP3A4 was fo und in bronchial glands, bronchiolar columnar and terminal epithelium, type II alveolar epithelium, and alveolar macrophages. These data est ablish that CYP3A5 is the predominant CYP3A form in human lung, that C YP3A4 is expressed in about 20% of individuals, and considerable varia tion of pulmonary expression occurs in both CYPs between individuals.