title: The human CYP1A1 gene is regulated in a developmental and tissue-specific fashion in transgenic mice.
abstract: 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.
authors.affiliation: Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego, La Jolla 92093, USA.
authors.forename: Alema
authors.initials: A
authors.lastname: Galijatovic
authors.forename: Deirdre
authors.initials: D
authors.lastname: Beaton
authors.forename: Nghia
authors.initials: N
authors.lastname: Nguyen
authors.forename: Shujuan
authors.initials: S
authors.lastname: Chen
authors.forename: Jessica
authors.initials: J
authors.lastname: Bonzo
authors.forename: Randall
authors.initials: R
authors.lastname: Johnson
authors.forename: Shin
authors.initials: S
authors.lastname: Maeda
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.forename: F Peter
authors.initials: FP
authors.lastname: Guengerich
authors.forename: Robert H
authors.initials: RH
authors.lastname: Tukey
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007774:Lactation; D008024:Ligands; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008957:Models, Genetic; D000072317:Polychlorinated Dibenzodioxins; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D008024:Ligands; D000072317:Polychlorinated Dibenzodioxins; D004247:DNA; D008156:Luciferases; D019363:Cytochrome P-450 CYP1A1