TRANSCRIPTION REGULATORY ELEMENTS IN THE MOUSE CYTOCHROME P-450 GENE

小鼠细胞色素P1450代谢多环芳烃，

The mouse cytochrome P1450 metabolizes polycyclic aromatic hydrocarbons, particularly carcinogens such as benzo(a)pyrene. These can be converted to highly reactive metabolites then can produce cellular damage and lead to cell transformation. Alternatively, other metabolites can be easily conjugated with glucuronic acid, glutathione, SO4 etc., and eliminated. The metabolic pathways through which a potential carcinogen enters depends largely on the concentration of P1450 and other P-450 species, epoxide hydratase, and conjugating enzymes in the cell. In order to understand the mechanisms by which P1450 levels can be elevated by drugs and chemical carcinogens, the cytochrome P1450 gene has been cloned. The whole gene has been sequenced including 1500 bp upstream of the genes cap site. Sequences associated with transcriptional regulation by 3-methyl-cholanthrene and 2,3,7,8 tetrachlorodibenzo-p-dioxane (TCDD) are being studied by use of the eukaryote expression vectors, pSV2-cat and pSV2-neo. DNA from the P1450 gene, including the RNA polymerase II promoter region, is fused to the choloramphenical acetyltransferase gene (CAT) and transfected into mouse hepa-1 cells. These cells have an active TCDD receptor and benzo(a)pyrene hydroxylase activity is readily induced. DNA deletion analysis and mutagenesis will be used to delineate regions of DNA associated with receptor-ligand interactions and transcriptional activation.