CONICET | Buscador de Institutos y Recursos Humanos

The well-known analgesic and antipyretic drug N-acetyl-p-aminophenol (acetaminophen; APAP) hasbeen previously reported to affect MDR1 expression in rat liver. In this study, we have investigatedthe effect of subtoxic doses of APAP on MDR1 expression and activity in rat intestine and humanintestinal cells. Administration of APAP at increasing doses of 0.2, 0.3, and 0.6 g/kg b.w., i.p. overthree consecutive days, induced MDR1 expression in rat duodenum (+240%) and ileum (+160%) asdetected by western blotting. This was accompanied by preserved localization of the protein at thesurface of the villus, as detected by confocal immunofluorescence microscopy. MDR1 activity wasincreased by 50% in APAP treated rats, as evaluated by serosal to mucosal secretion of rhodamine 123in everted intestinal sacs. Treatment with APAP also decreased by 65% the portal vein concentrationsof digoxin found in anesthetized rats after intraduodenal administration of this drug, which isconsistent 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 enhancedability (+78%) to reduce intracellular content of rhodamine 123. Taken together these data suggestthe existence of APAP-induced stimulation of MDR1 transcription in the intestinal epithelium. Thesefindings are of clinical relevance, as co-administration of APAP with other MDR1 substrates couldindirectly inhibit the net intestinal absorption of these drugs, leading to changes in theirpharmacokinetics and therapeutic efficacy.