Murine mdr-1, mdr-2, and mdr-3 gene expression: no coinduction with the Cyp1a-1 and Nmo-1 genes in liver by 2,3,7,8-tetrachlorodibenzo-p-dioxin.
Multidrug-resistance (MDR) genes are induced in the liver of rodents treated with a variety of foreign chemicals and hepatocarcinogens. It has been reported that 2,3,6,7-tetrachlorodibenzo-p-dioxin (TCDD) might increase hepatic MDR transcripts in the Fischer rat and the C57BL/6 (B6) inbred mouse strain having the high-affinity aromatic hydrocarbon (Ah) receptor, but not in the DBA/2 (D2) strain having the low-affinity Ah receptor. These intriguing results suggest that TCDD might activate MDR gene expression by way of an Ah receptor-mediated signal transduction pathway. We have attempted to confirm these data in four inbred mouse strains: two (B6 and BALB/c) having the high-affinity Ah receptor, and two (D2 and AKR) having the low-affinity Ah receptor. The RNase protection assay was used to distinguish between the MDR1, MDR2, and MDR3 mRNAs. TCDD treatment at high (100 micrograms/kg) and low (1 mu/kg) doses, a time course from 6 to 96 hr of TCDD treatment, progeny from the B6D2F1 x D2 backcross, and transcriptional run-on experiments were performed. The Cyp1a-1 (cytochrome P1450) and Nmo-1 [NAD(P)H:menadione oxidoreductase] genes, two members of the TCDD-inducible [Ah] battery, were used as positive controls. We were unable to detect significant coinduction of MDR1, MDR2, or MDR3 mRNA with CYP1A1 mRNA or with Cyp1a-1 or Nmo-1 transcription under any conditions. Therefore, we conclude that any effects that TCDD might have on MDR expression must be substantially different from TCDD effects on genes known to be induced via the Ah receptor.
Teeter
L D
LD
Department of Molecular Pathology, University of Texas M.D. Anderson Cancer Center, Houston, 77030.
Petersen
D D
DD
Nebert
D W
DW
Kuo
M T
MT
D000818:Animals; D003001:Cloning, Molecular; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D011808:Quinone Reductases / Q000235:genetics*; D015347:RNA Probes; D012333:RNA, Messenger / Q000378:metabolism; D013698:Templates, Genetic; D014158:Transcription, Genetic
D000072317:Polychlorinated Dibenzodioxins; D015347:RNA Probes; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D011808:Quinone Reductases