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Research ArticleArticle

Tissue Distribution and Chemical Induction of Multiple Drug Resistance Genes in Rats

James M. Brady, Nathan J. Cherrington, Dylan P. Hartley, Susan C. Buist, Ning Li and Curtis D. Klaassen
Drug Metabolism and Disposition July 2002, 30 (7) 838-844; DOI: https://doi.org/10.1124/dmd.30.7.838
James M. Brady
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Nathan J. Cherrington
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Dylan P. Hartley
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Susan C. Buist
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Ning Li
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Curtis D. Klaassen
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Abstract

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.

Footnotes

  • ↵1 Current address: Department of Drug Metabolism, Merck Research Laboratories, Mail Stop RY80D-100, Rahway, NJ 07065.

  • Supported by National Institutes of Health Grants ES-09716, ES-03192, ES-05883011, training Grant ES-07079, and Lied Foundation Grant 559086.

  • Abbreviations used are::
    P-gp
    P-glycoproteins
    mdr
    multiple drug resistance
    AhR
    aryl hydrocarbon receptor
    TCDD
    2,3,7,8-tetrachlorodibenzo-p-dioxin
    I3C
    indole-3-carbinol
    BNF
    β-naphthaflavone
    PCB
    polychlorinated biphenyl
    CAR
    constitutive androstane receptor
    PB
    phenobarbital
    DAS
    diallyl sulfide
    PXR
    pregnane X receptor
    PCN
    pregnenolone-16α-carbonitrile
    Spir
    spironolactone
    Dex
    dexamethasone
    PPAR
    peroxisome proliferator-activated receptor
    Clof
    clofibrate
    DEHP
    diethylhexylphthalate
    PFDA
    perfluorodecanoic acid
    EpRE
    electrophile response element
    EQ
    ethoxyquin
    OPZ
    oltipraz
    INH
    isoniazid
    ASA
    acetylsalicylic acid
    STZ
    streptozotocin
    ANOVA
    analysis of variance
    • Received January 2, 2002.
    • Accepted April 11, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (7)
Drug Metabolism and Disposition
Vol. 30, Issue 7
1 Jul 2002
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Research ArticleArticle

Tissue Distribution and Chemical Induction of Multiple Drug Resistance Genes in Rats

James M. Brady, Nathan J. Cherrington, Dylan P. Hartley, Susan C. Buist, Ning Li and Curtis D. Klaassen
Drug Metabolism and Disposition July 1, 2002, 30 (7) 838-844; DOI: https://doi.org/10.1124/dmd.30.7.838

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Research ArticleArticle

Tissue Distribution and Chemical Induction of Multiple Drug Resistance Genes in Rats

James M. Brady, Nathan J. Cherrington, Dylan P. Hartley, Susan C. Buist, Ning Li and Curtis D. Klaassen
Drug Metabolism and Disposition July 1, 2002, 30 (7) 838-844; DOI: https://doi.org/10.1124/dmd.30.7.838
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