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Research ArticleArticle

Tissue Distribution, Gender-Divergent Expression, Ontogeny, and Chemical Induction of Multidrug Resistance Transporter Genes (Mdr1a, Mdr1b, Mdr2) in Mice

Yue Julia Cui, Xingguo Cheng, Yi Miao Weaver and Curtis D. Klaassen
Drug Metabolism and Disposition January 2009, 37 (1) 203-210; DOI: https://doi.org/10.1124/dmd.108.023721
Yue Julia Cui
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Xingguo Cheng
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Yi Miao Weaver
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Curtis D. Klaassen
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Abstract

Multidrug resistance (Mdr) transporters are ATP-binding cassette transporters that efflux amphipathic cations from cells and protect tissues from xenobiotics. Unfortunately, Mdr transporters also efflux anticancer drugs from some tumor cells, resulting in multidrug resistance. There are two groups of Mdrs in mice: group I includes Mdr1a and Mdr1b that transport xenobiotics, whereas group II is Mdr2, a flipase that facilitates phospholipid excretion into bile. Little is known about the regulation of Mdr genes in vivo. The purpose of this study was to determine tissue distribution, gender differences, ontogeny, and chemical induction of Mdrs in mice. The mRNA of Mdr1a is highest in gastrointestinal tract, Mdr1b in ovary and placenta, and Mdr2 in liver. Both Mdr1a and Mdr1b in kidney show female-predominant expression patterns due to repression by androgens. The ontogeny of mouse Mdr1a in duodenum and brain as well as Mdr1b in brain, kidney, and liver all share a similar developmental pattern: low expression at birth, followed by a gradual increase to mature levels at approximately 30 days of age. In contrast, Mdr2 mRNA in liver is markedly up-regulated at birth, which returns to low levels by 5 days of age and then gradually increases to mature levels. None of the Mdrs in liver are readily inducible by any class of microsomal enzyme inducers. In conclusion, the three Mdr transporters in mice are expressed in a tissue-specific and age-dependent pattern, there are gender differences in expression, and Mdr transporters are inducible by only a few microsomal enzyme inducers.

Footnotes

  • This work was supported by National Institutes of Health [Grants ES-09649, ES-09716, and RR021940].

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.108.023721.

  • ABBREVIATIONS: Mdr, multidrug resistance; GI, gastrointestinal; GH, growth hormone; MEI, microsomal enzyme inducer; AhR, aryl hydrocarbon receptor; CAR, constitutive androstane receptor; PXR, pregnane X receptor; PPAR, peroxisome proliferator-activated receptor; Nrf2, nuclear factor erythroid 2-related factor 2; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; PCB126, polychlorinated biphenyl 126; lit-lit, growth hormone-releasing hormone receptor-deficiency; DHT, 5α-dihydroxytestosterone; E2, 11β-estradiol; GHRH, growth hormone-releasing hormone; BNF, β-naphthoflavone; PB, phenobarbital; TCPOBOP, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene; DAS, diallyl sulfide; PCN, pregnenolone-16α-carbonitrile; SPR, spironolactone; CLFB, clofibric acid; CPFB, ciprofibrate; DEHP, diethylhexylphthalate; BHA, butylated hydroxyanisole; OPZ, oltipraz; bDNA, branched DNA; ANOVA, analysis of variance; FXR, farnesoid X receptor; FPGH, female-patterned growth hormone; GNX, gonadectomy; HX, hypophysectomy; MPGH, male-patterned growth hormone.

    • Received August 7, 2008.
    • Accepted October 9, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 37 (1)
Drug Metabolism and Disposition
Vol. 37, Issue 1
1 Jan 2009
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Research ArticleArticle

Tissue Distribution, Gender-Divergent Expression, Ontogeny, and Chemical Induction of Multidrug Resistance Transporter Genes (Mdr1a, Mdr1b, Mdr2) in Mice

Yue Julia Cui, Xingguo Cheng, Yi Miao Weaver and Curtis D. Klaassen
Drug Metabolism and Disposition January 1, 2009, 37 (1) 203-210; DOI: https://doi.org/10.1124/dmd.108.023721

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Research ArticleArticle

Tissue Distribution, Gender-Divergent Expression, Ontogeny, and Chemical Induction of Multidrug Resistance Transporter Genes (Mdr1a, Mdr1b, Mdr2) in Mice

Yue Julia Cui, Xingguo Cheng, Yi Miao Weaver and Curtis D. Klaassen
Drug Metabolism and Disposition January 1, 2009, 37 (1) 203-210; DOI: https://doi.org/10.1124/dmd.108.023721
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