| Ethynylestradiol increases expression and activity of rat liver MRP3. | |
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MedLine Citation:
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PMID: 16554369 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We evaluated the effect of ethynylestradiol (EE) administration (5 mg/kg b.wt. s.c., for 5 consecutive days) on the expression and activity of multidrug resistance-associated protein 3 (Mrp3) in rats. Western blotting analysis revealed decreased Mrp2 (-41%) and increased Mrp3 (+200%) expression by EE. To determine the functional impact of up-regulation of Mrp3 versus Mrp2, we measured the excretion of acetaminophen glucuronide (APAP-glu), a common substrate for both transporters, into bile and perfusate in the recirculating isolated perfused liver (IPL) model. APAP-glu was generated endogenously from acetaminophen (APAP), which was administered as a tracer dose (2 micromol/ml) into the perfusate. Biliary excretion of APAP-glu after 60 min of perfusion was reduced in EE-treated rats (-80%). In contrast, excretion into the perfusate was increased by EE (+45%). Liver content of APAP-glu at the end of the experiment was reduced by 36% in the EE group. The total amount of glucuronide remained the same in both groups. Taken together, these results indicate that up-regulation of Mrp3 led to an exacerbated basolateral versus canalicular excretion of conjugated APAP in IPL. We conclude that induced expression of basolateral Mrp3 by EE may represent a compensatory mechanism to prevent intracellular accumulation of common Mrp substrates, either endogenous or exogenous, due to reduced expression and activity of apical Mrp2. |
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Authors:
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María L Ruiz; Silvina S M Villanueva; Marcelo G Luquita; Mary Vore; Aldo D Mottino; Viviana A Catania |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2006-03-22 |
Journal Detail:
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Title: Drug metabolism and disposition: the biological fate of chemicals Volume: 34 ISSN: 0090-9556 ISO Abbreviation: Drug Metab. Dispos. Publication Date: 2006 Jun |
Date Detail:
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Created Date: 2006-05-19 Completed Date: 2006-07-31 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 9421550 Medline TA: Drug Metab Dispos Country: United States |
Other Details:
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Languages: eng Pagination: 1030-4 Citation Subset: IM |
Affiliation:
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Instituto de Fisiología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Argentina. |
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| MeSH Terms | |
Descriptor/Qualifier:
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ATP-Binding Cassette Transporters
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biosynthesis,
metabolism Acetaminophen / analogs & derivatives, analysis, metabolism Animals Bile / drug effects, secretion Ethinyl Estradiol / pharmacology* Liver / drug effects*, metabolism Male Multidrug Resistance-Associated Proteins / biosynthesis, metabolism* Perfusion Rats Rats, Wistar Time Factors Up-Regulation |
| Chemical | |
Reg. No./Substance:
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0/ATP-Binding Cassette Transporters; 0/Abcc2 protein, rat; 0/Multidrug Resistance-Associated Proteins; 0/multidrug resistance-associated protein 3; 103-90-2/Acetaminophen; 16110-10-4/acetaminophen glucuronide; 57-63-6/Ethinyl Estradiol |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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