The human CYP1A1 gene is regulated in a developmental and tissue-specific fashion in transgenic mice.

Galijatovic A, Beaton D, Nguyen N, Chen S, Bonzo J, Johnson R, Maeda S, Karin M, Guengerich FP, Tukey RH
J Biol Chem. 2004 279 (23): 23969-76

PMID: 15037607 · DOI:10.1074/jbc.M400973200

Regulation and expression of human CYP1A1 is demonstrated in transgenic mice. We have developed two transgenic mouse lines. One mouse strain (CYPLucR) carries a functional human CYP1A1 promoter (-1612 to +293)-luciferase reporter gene, and the other strain (CYP1A1N) expresses CYP1A1 under control of the full-length human CYP1A1 gene and 9 kb of flanking regulatory DNA. With CYPLucR(+/-) mice, 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD) and several other aryl hydrocarbon receptor ligands induced hepatocyte-specific luciferase activity. When other tissues were examined, TCDD induced luciferase activity in brain with limited induction in lung and no detectable luciferase activity in kidney. Treatment of CYP1A1N(+/-) mice with TCDD resulted in induction of human CYP1A1 in liver and lung, while mouse Cyp1a1 was induced in liver, lung, and kidney. Although induced CYP1A1/Cyp1a1 could not be detected by Western blot analysis in brains from CYP1A1N(+/-) mice, induction in brain was verified by detection of CYP1A1/Cyp1a1 RNA. The administration of TCDD to nursing mothers to examine the effect of lactational exposure via milk demonstrated prominent induction of luciferase activity in livers of CYPLucR(+/-) newborn pups with limited induction in brain. However, TCDD treatment of adult CYPLucR(+/-) mice led to a 7-10-fold induction of brain luciferase activity. Combined these results indicate that tissue-specific and developmental factors are controlling aryl hydrocarbon receptor-mediated induction of human CYP1A1.

MeSH Terms (27)

Animals Animals, Newborn Blotting, Western Brain Cell Line Cells, Cultured Cytochrome P-450 CYP1A1 DNA Gene Expression Regulation, Developmental Hepatocytes Humans Kidney Lactation Ligands Liver Luciferases Lung Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Transgenic Models, Genetic Polychlorinated Dibenzodioxins Promoter Regions, Genetic Reverse Transcriptase Polymerase Chain Reaction Time Factors Tissue Distribution

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