The human CYP1A1 gene is regulated in a developmental and tissue-specific fashion in transgenic mice.
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.
Galijatovic
Alema
A
Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego, La Jolla 92093, USA.
Beaton
Deirdre
D
Nguyen
Nghia
N
Chen
Shujuan
S
Bonzo
Jessica
J
Johnson
Randall
R
Maeda
Shin
S
Karin
Michael
M
Guengerich
F Peter
FP
Tukey
Robert H
RH
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
D008024:Ligands; D000072317:Polychlorinated Dibenzodioxins; D004247:DNA; D008156:Luciferases; D019363:Cytochrome P-450 CYP1A1