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Vol. 300, Issue 1, 97-104, January 2002
University of Kansas Medical Center, Kansas City, Kansas
Many phase I and II microsomal enzyme inducers share common mechanisms
of transcriptional activation and thus share a similar battery of genes
that are coordinately regulated. Many phase II metabolites are
thought to be transported out of cells by multidrug resistance proteins
1, 2, and 3 (Mrp1, 2, and 3). The purpose of this study was to
determine the organ distribution of these three transporters in rat,
and whether they are coordinately regulated with phase I and II
drug-metabolizing enzymes. Therefore, Mrp1, 2, and 3 mRNAs were
quantified using branched DNA signal amplification in multiple tissues
and in tissues from rats that were treated with 18 chemicals thought to
induce drug-metabolizing enzymes by six different transcription
activation mechanisms [aryl-hydrocarbon receptor ligands, constitutive
androstane receptor (CAR) activators, pregnane-X-receptor ligands,
peroxisome proliferator activator receptor ligands, electrophile
response element (EpRE) activators, and CYP2E1 inducers]. It was found
that Mrp1 was expressed at a high level in kidney, lung, intestine, and
brain, with low expression in liver. Mrp2 was highly expressed in liver
and duodenum, and Mrp3 was highly expressed throughout the intestine
but very low in liver. Microsomal enzyme inducers did not markedly
increase the expression of Mrp1 or Mrp2. However, Mrp3 expression was
significantly increased by each of the CAR activators and an EpRE
activator in liver. Mrp3 was not similarly induced in kidney and large
intestine, demonstrating that the coordinate inducibility of Mrp3 is
specific to the liver. We conclude that rat hepatic Mrp3 is induced by CAR activators, thus enhancing the vectoral excretion of some phase II
metabolites from the liver to the blood.
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