Abstract
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.
Footnotes
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↵1 Current address: Department of Drug Metabolism, Merck Research Laboratories, Mail Stop RY80D-100, Rahway, NJ 07065.
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↵2 Current address: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655.
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This work was supported by National Institutes of Health Grants ES-09716 and ES-03192, and by National Institutes of Health Training Grant ES-07079 (to N.J.C., D.P.H., and D.R.J.) and Grant ES-05883 (to N.J.C.).
Abbreviations
- Mrp
- multidrug resistance protein
- CAR
- constitutive androstane receptor
- EpRE
- electrophile response element
- TCDD
- 2,3,7,8-tetrachlorodibenzo-p-dioxin
- PCB 99
- 2,2′,4,4′,5-pentachlorobiphenyl
- PCB 126
- 3,3′,4,4′,5-pentachlorobiphenyl
- PCN
- pregnenolone 16α-carbonitrile
- bDNA
- branched DNA
- APAP
- acetaminophen
- Received June 8, 2001.
- Accepted September 21, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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