Induction of intestinal P‐glycoprotein (Pgp) expression and activity by sub‐toxic doses of acetaminophen (AP) in rat intestine and human LS174T cells

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AP induced liver Pgp expression and activity in rats.Aimto study the effect of sub‐toxic doses of AP on intestinal Pgp expression in rats and in a human intestinal cell line.M&MMale Wistar rats were injected i.p. for 3 days with 0.2; 0.3; and 0.6 g/kg b.w. of AP (AP group) or vehicle (C group) (n=4). One day later Pgp expression and activity were evaluated by western‐blotting and rhodamine 123 (R123, 15 uM) serosal to mucosal transport in ileum isolated sacs with or without verapamil (V, 100 uM). Intestinal human LS174T cells were exposed to a sub‐toxic dose of AP (5 mM) for 48 hs, then Pgp expression was evaluated by QPCR and R123 efflux was determined by flow citometry with or without V.ResultsIleum Pgp expression increased in AP vs C (160%, P<0.05). Cumulative R123 secretion was 44% higher in AP group (P<0.05). V inhibited R123 transport in both AP and C. Cells exposed to AP expressed 60% more protein and presented 80% more activity than control cells (P<0.05).ConclusionSub‐toxic doses of AP induced intestinal Pgp expression and activity in rats and in a human intestinal cell line. This suggests potential drug‐drug interactions when AP is co‐administered with other Pgp substrates. Consistently, preliminary studies have shown induction of Pgp in a human intestinal cell line exposed to sub‐toxic concentrations of APAP.