Teeter L D, Petersen D D, Nebert D W, Kuo M T
Department of Molecular Pathology, University of Texas M.D. Anderson Cancer Center, Houston, 77030.
DNA Cell Biol. 1991 Jul-Aug;10(6):433-41. doi: 10.1089/dna.1991.10.433.
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.
多药耐药（MDR）基因在经多种外来化学物质和肝癌致癌物处理的啮齿动物肝脏中被诱导。据报道，2,3,6,7-四氯二苯并对二恶英（TCDD）可能会增加具有高亲和力芳烃（Ah）受体的Fischer大鼠和C57BL/6（B6）近交系小鼠肝脏中的MDR转录本，但在具有低亲和力Ah受体的DBA/2（D2）品系中则不会。这些有趣的结果表明，TCDD可能通过Ah受体介导的信号转导途径激活MDR基因表达。我们试图在四种近交系小鼠品系中证实这些数据：两种（B6和BALB/c）具有高亲和力Ah受体，另外两种（D2和AKR）具有低亲和力Ah受体。核糖核酸酶保护试验用于区分MDR1、MDR2和MDR3 mRNA。进行了高剂量（100微克/千克）和低剂量（1微克/千克）的TCDD处理、TCDD处理6至96小时的时间进程、B6D2F1×D2回交后代以及转录延伸实验。Cyp1a-1（细胞色素P1450）和Nmo-1 [NAD(P)H：甲萘醌氧化还原酶]基因是TCDD诱导型[Ah]基因家族的两个成员，用作阳性对照。在任何条件下，我们都无法检测到MDR1、MDR2或MDR3 mRNA与CYP1A1 mRNA或与Cyp1a-1或Nmo-1转录的显著共诱导。因此，我们得出结论，TCDD对MDR表达可能产生的任何影响必定与TCDD对已知通过Ah受体诱导的基因的影响有很大不同。
