Regulation of CYP3A genes in the human respiratory tract.

The CYP3A gene cluster consists of four members, CYP3A4, CYP3A5, CYP3A7 and CYP3A43. Especially the CYP3A4 and CYP3A5 enzymes play a significant role in the metabolism of numerous exogenous (drugs, pollutants, procarcinogens) and endogenous (steroids, bile acids) compounds. CYP3A5 protein is present in the liver and some extrahepatic tissues, such as the gut wall, kidney, adrenal gland, prostate and many cell types in the lung. In the lung, the highest amounts of CYP3A5 protein are present in bronchial and alveolar epithelial cells, bronchial glands and alveolar macrophages. The same cells types have little or no CYP3A4 expression. Cigarette smoking markedly represses CYP3A5 content in alveolar macrophages. CYP3A5 is upregulated by glucocorticoids via the glucocorticoid receptor (GR) in lung adenocarcinoma derived A549 cells. Tissue selective distribution of CYP3A4 is controlled by tissue enriched transcription factors, such as hepatic nuclear factor 4alpha (HNF4alpha), and ligand dependent nuclear receptors, most notably pregnane X receptor (PXR) and constitutive androstane receptor (CAR). The selective expression of CYP3A5 over CYP3A4 in specific lung cells is likely to be the sum of the effects of tissue-specific upregulating and downregulating transcription factors in these cells. Since the CYP3A4/5 enzymes mediate the metabolism of many exogenous and endogenous compounds with direct relevance to pulmonary physiology and pathology, the functions of these enzymes and factors controlling them should be elucidated in much more detail.