Differential gene expression in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Noncoordinate regulation of a TCDD-induced aldehyde dehydrogenase and cytochrome P-450c in the rat.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) regulates the transcription of a specific subset of genes through a receptor-mediated mechanism. We have isolated a cDNA to a TCDD-inducible rat liver aldehyde dehydrogenase and have shown that its induction by TCDD differs from that of another TCDD-induced gene, cytochrome P-450c, with regard to dose-response relationship, induction kinetics, and tissue specificity. At least a 10-fold higher dose of TCDD was required for half-maximal induction of TCDD-inducible rat liver aldehyde dehydrogenase in rat liver than the dose that half-maximally induced cytochrome P-450c. Further, the kinetics of induction of TCDD-inducible rat liver aldehyde dehydrogenase by TCDD in rat liver was delayed compared with that of cytochrome P-450c. Striking discrepancies were found in the capacity of various organs to induce both TCDD-inducible rat liver aldehyde dehydrogenase and cytochrome P-450c in a coordinated manner in response to TCDD. Organs that were able to evoke one of these responses to TCDD were not necessarily able to evoke coordinately the other response. The capacity of an organ to exhibit either of these two responses to TCDD did not correlate stringently with reported Ah receptor abundance. Our data suggest that TCDD can modulate the expression of specific genes in different ways and that regulatory pathways in addition to the classically defined Ah receptor may be involved.
Dunn
T J
TJ
Department of Oncology, McArdle Laboratory for Cancer Research, Medical School, University of Wisconsin, Madison 53706.
Lindahl
R
R
Pitot
H C
HC
D000444:Aldehyde Dehydrogenase / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D003001:Cloning, Molecular; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D004147:Dioxins / Q000494:pharmacology*; D004790:Enzyme Induction; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D005796:Genes / Q000187:drug effects*; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008114:Liver Neoplasms, Experimental / Q000201:enzymology*; D008297:Male; D009928:Organ Specificity; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D014176:Protein Biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D014158:Transcription, Genetic / Q000187:drug effects*
D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D000444:Aldehyde Dehydrogenase