Tissue distribution and chemical induction of multiple drug resistance genes in rats
Tissue distribution and chemical induction of multiple drug resistance genes in rats
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DOI：
10.1124/dmd.30.7.838
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发表时间：
2002-07-01
影响因子：
3.9
通讯作者：
Klaassen, CD
中科院分区：
文献类型：
--
作者：
Brady, JM;Cherrington, NJ;Klaassen, CD
多重耐药（mdr）基因编码P-糖蛋白，它负责对某些癌症化疗药物的耐药性和细胞外源性物质的流出。因此，多重耐药可以保护器官免受异生素的侵害。在大鼠中，有两个能够进行异生素转运的 mdr1 基因：mdr1a 和 mdr1b。本研究的目的是确定大鼠 mdr1a 和 mdr1b mRNA 的组织分布，以及增加 I 期和 II 期药物代谢酶的微粒体酶诱导剂是否协调调节 mdr1a 和/或 mdr1b。使用分支 DNA 信号放大技术测定 mdr1a 和 mdr1b 的 mRNA 水平。 mdr1a mRNA 的表达水平在胃肠道中最高，从十二指肠、空肠、回肠到大肠，其水平分别增加。大脑皮层、小脑、肾脏、肺和肝脏中mdr1a mRNA的表达水平不到回肠的十分之一。 mdr1b mRNA 的组织分布与 mdr1a 相似，在胃肠道中表达量最高，但仅比大多数其他组织高出约 3 倍。通过用 18 种代表芳烃受体配体、组成型雄甾烷受体配体、孕烷 X 受体配体、过氧化物酶体增殖物激活受体配体、亲电反应元件激活剂和 CYP4502E1 诱导剂的化学物质处理大鼠，评估了肝脏、肾脏和回肠中 mdr1a 和 mdr1b mRNA 转录物的诱导。用任何此类配体治疗大鼠，mdr1a 和 mdr1b mRNA 的肝、肾和肠表达均未显着改变。总之，大鼠 mdr1 基因的主要表达是在胃肠道中，它们被认为具有减少某些外源物质吸收的功能。通过与 I 相和 II 相药物代谢酶的协调机制，微粒体酶诱导剂不容易增加大鼠 mdr1 基因的表达。
Multiple drug resistance (mdr) genes encode P-glycoprotein, which is responsible for resistance to some cancer chemotherapeutic drugs and efflux of xenobiotics of cells. Thus, mdr can protect organs from xenobiotics. In rats, there are two mdr1 genes capable of xenobiotic transport, mdr1a and mdr1b. The purpose of this study was to determine the tissue distribution of rat mdr1a and mdr1b mRNA and whether microsomal enzyme inducers that increase phase I and II drug-metabolizing enzymes coordinately regulate mdr1a and/or mdr1b. The mRNA levels of mdr1a and mdr1b were determined using branched-DNA signal amplification technology. The highest level of expression of mdr1a mRNA was observed in the gastrointestinal tract, with levels increasing, respectively, from duodenum, jejunum, and ileum to large intestine. Expression levels of mdr1a mRNA in the cerebral cortex, cerebellum, kidney, lung, and liver were less than one-tenth of that in the ileum. The tissue distribution of mdr1b mRNA was similar to mdr1a with highest expression in the gastrointestinal tract but only about 3-fold higher than in most other tissues. The induction of mdr1a and mdr1b mRNA transcripts in liver, kidney, and ileum by treatment of rats with 18 chemicals representing aryl hydrocarbon receptor ligands, constitutive androstane receptor ligands, pregnane X receptor ligands, peroxisome proliferator-activated receptor ligands, electrophile-response-element activators, and CYP4502E1 inducers was assessed. Hepatic, renal, and intestinal expression of mdr1a and mdr1b mRNA were not significantly altered by treatment of rats with any of these classes of ligands. In conclusion, the primary expression of rat mdr1 genes is in the gastrointestinal tract where they are thought to function to decrease the absorption of some xenobiotics. Rat mdr1 gene expression is not readily increased by microsomal enzyme inducers in rats through coordinate mechanisms with phase I and II drug-metabolizing enzymes.