Acetaminophen-induced stimulation of MDR1 expression and activity in rat intestine and in LS 174T human intestinal cell line
| Autor: | Silvina Stella Maris Villanueva, Alba G. Blazquez, Aldo D. Mottino, Jose J.G. Marin, Modesto C. Rubio, Griselda Delli Carpini, Analia Novak, Carolina Inés Ghanem, Agostina Arias |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Digoxin medicine.medical_specialty Cardiotonic Agents Ileum Stimulation Biochemistry Rhodamine 123 Intestinal absorption Cell Line chemistry.chemical_compound Pharmacokinetics Internal medicine polycyclic compounds medicine Animals Humans ATP Binding Cassette Transporter Subfamily B Member 1 Rats Wistar Acetaminophen P-glycoprotein Pharmacology Dose-Response Relationship Drug biology digestive oral and skin physiology Biological Transport Analgesics Non-Narcotic Intestinal epithelium Rats Intestines medicine.anatomical_structure Endocrinology Gene Expression Regulation chemistry biology.protein medicine.drug |
| Zdroj: | Biochemical Pharmacology. 81:244-250 |
| ISSN: | 0006-2952 |
| Popis: | The well-known analgesic and antipyretic drug N-acetyl-p-aminophenol (acetaminophen; APAP) has been previously reported to affect MDR1 expression in rat liver. In this study, we have investigated the effect of subtoxic doses of APAP on MDR1 expression and activity in rat intestine and human intestinal cells. Administration of APAP at increasing doses of 0.2, 0.3, and 0.6 g/kg b.w., i.p. over three consecutive days, induced MDR1 expression in rat duodenum (+240%) and ileum (+160%) as detected by western blotting. This was accompanied by preserved localization of the protein at the surface of the villus, as detected by confocal immunofluorescence microscopy. MDR1 activity was increased by 50% in APAP treated rats, as evaluated by serosal to mucosal secretion of rhodamine 123 in everted intestinal sacs. Treatment with APAP also decreased by 65% the portal vein concentrations of digoxin found in anesthetized rats after intraduodenal administration of this drug, which is consistent with an APAP-induced increased efficacy of intestinal barrier for digoxin net absorption. Exposure of LS 174T human colon adenocarcinoma cells to subtoxic APAP concentration (5 mM) induced an increase in MDR1 mRNA expression (+46%), which was accompanied with an enhanced ability (+78%) to reduce intracellular content of rhodamine 123. Taken together these data suggest the existence of APAP-induced stimulation of MDR1 transcription in the intestinal epithelium. These findings are of clinical relevance, as co-administration of APAP with other MDR1 substrates could indirectly inhibit the net intestinal absorption of these drugs, leading to changes in their pharmacokinetics and therapeutic efficacy. |
| Databáze: | OpenAIRE |
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