Differential induction of Cyp1a1, Cyp1b1, Ahd4, and Nmo1 in murine skin tumors and adjacent normal epidermis by ligands of the aryl hydrocarbon receptor.
Products of several phase I and II genes transcriptionally activated by ligands of the aryl hydrocarbon receptor (AHR) were quantitated in cutaneous samples isolated from non-tumor-bearing SENCAR or SSIN mice, and animals bearing skin tumors generated in initiation-promotion protocols. The constitutive 7-ethoxyresorufin O-deethylase (EROD) activities in papillomas and squamous cell carcinomas were less than or equal to 37% of the values measured in the adjacent normal cutaneoustissue. Dermal and epidermal EROD specific activities in microsomal samples prepared from both tumor-bearing and non-tumor-bearing mice were elevated 9- to 14- and 43- to 77-fold, respectively, above constitutive levels 16-20 h after a single topical application of 100 nmol of dibenz[a,c]anthracene (DB[a,c]A). EROD specific activities in tumors were maximally elevated two-fold after topical application of DB[a,c]A. Western blot, northern blot, and reverse transcription (RT)-polymerase chain reaction (PCR) analyses confirmed that the EROD measurements reflected cutaneous cytochrome P450 (CYP) 1A1 protein, mature mRNA, and heterogeneous nuclear RNA contents, respectively. Analyses of CYP1A1, CYP1B1, cytosolic aldehyde dehydrogenase class 3, and NAD(P)H:menadione oxidoreductase (NMO1) mRNA content by RT-PCR revealed significant increases in all four mRNAs in the normal tissue adjacent to papillomas after exposure to 4 nmol of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) but no increases in the tumors. NMO1 mRNA content in acetone-treated papillomas approached the levels detected in TCDD-treated normal skin. RT-PCR analyses also demonstrated elevated constitutive aryl hydrocarbon receptor nuclear translocator mRNA content (an approximately two-fold increase) in skin tumors. In contrast, AHR mRNA content in the tumors was about 20% of that measured in adjacent normal tissue. Collectively, these studies demonstrated that ligand-induced, AHR-mediated processes are absent in murine skin tumors that develop in initiation-promotion protocols.
Reiners
J J
JJ
Institute of Chemical Toxicology, Wayne State University, Detroit, Michigan 48201, USA.
Jones
C L
CL
Hong
N
N
Myrand
S P
SP
D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001551:Benz(a)Anthracenes / Q000494:pharmacology; D002273:Carcinogens; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D004790:Enzyme Induction; D004817:Epidermis / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D008024:Ligands; D051379:Mice; D020928:Mitogen-Activated Protein Kinases; D010212:Papilloma / Q000235:genetics; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*; D012878:Skin Neoplasms / Q000235:genetics*
D000444:Aldehyde Dehydrogenase; D001189:Aryl Hydrocarbon Hydroxylases; D001551:Benz(a)Anthracenes; D002273:Carcinogens; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System; D008024:Ligands; D020928:Mitogen-Activated Protein Kinases; D000072317:Polychlorinated Dibenzodioxins; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D018336:Receptors, Aryl Hydrocarbon; C006710:benzotriphenylene; C585498:Cyp1b1 protein, mouse; C105543:Aldh3a1 protein, mouse