Acetaminophen-induced stimulation of MDR1 expression and activity in rat intestine and in LS 174T human intestinal cell line.

GHANEM CI; ARIAS A; NOVAK A; DELLICARPINI G; VILLANUEVA SS; BLAZQUEZ AG; MARIN JJ; MOTTINO AD; RUBIO MC

BIOCHEMICAL PHARMACOLOGY

PERGAMON-ELSEVIER SCIENCE LTD

Año: 2010 p. 244 - 250

0006-2952

The well-known analgesic and antipyretic drug N-acetyl-p-aminophenol(acetaminophen; APAP) has been previously reported to affect MDR1 expression inrat liver. In this study, we have investigated the effect of subtoxic doses ofAPAP on MDR1 expression and activity in rat intestine and human intestinal cells.Administration of APAP at increasing doses of 0.2, 0.3, and 0.6g/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 confocalimmunofluorescence microscopy. MDR1 activity was increased by 50% in APAP treatedrats, as evaluated by serosal to mucosal secretion of rhodamine 123 in evertedintestinal sacs. Treatment with APAP also decreased by 65% the portal veinconcentrations of digoxin found in anesthetized rats after intraduodenaladministration of this drug, which is consistent with an APAP-induced increasedefficacy of intestinal barrier for digoxin net absorption. Exposure of LS 174Thuman colon adenocarcinoma cells to subtoxic APAP concentration (5mM) induced an increase in MDR1 mRNA expression (+46%), which was accompanied with an enhancedability (+78%) to reduce intracellular content of rhodamine 123. Taken togetherthese data suggest the existence of APAP-induced stimulation of MDR1transcription in the intestinal epithelium. These findings are of clinicalrelevance, as co-administration of APAP with other MDR1 substrates couldindirectly inhibit the net intestinal absorption of these drugs, leading tochanges in their pharmacokinetics and therapeutic efficacy.