title: The mechanism of the down-regulation of hepatic transporters in rats with indomethacin-induced intestinal injury.
abstract: BACKGROUND
  Previously, we reported that hepatic transporters were down-regulated consistent with intestinal injury in indomethacin (IDM)-treated rats.
  
  
  OBJECTIVE
  The purpose of this study was to characterize this mechanism of the down-regulation of hepatic transporters in IDM-treated rats.
  
  
  METHODS
  Hepatic nuclear receptor expressions, oxidative stress condition and the expression of hepatic transporters were evaluated in rats with IDM-induced intestinal injury with or without the administration of mucosal protectant ornoprostil, a prostaglandin E1 analogue, or aminoguanidine (AG), an iNOS inhibitor.
  
  
  RESULTS
  All the nuclear receptors examined in the present study, which regulates hepatic transporters, were decreased by the administration of IDM. Hepatic glutathione, an indicator of oxidative stress, was significantly reduced compared with control. We then determined the expression of hepatic transporters by semi-quantitative real-time RT-PCR and Western blot analysis in IDM-treated rats with or without the administration of ornoprostil or AG. Ornoprostil recovered the gene expression of Oatp1a1, Oatp1b2 and Mrp2 and protein expression of Mrp2 while it had no effect on Oatp1a1 and Oatp1b2 proteins. These results indicated that the gene expression of hepatic transporters was down-regulated in association with the intestinal injury. On the other hand, there is no effect of AG on the reduced gene expression of hepatic Oatp1a1, Oatp1b2 and Mrp2. In protein expression, AG slightly recovered Mrp2 expression accompanied by a partial decrease in portal NO levels.
  
  
  CONCLUSIONS
  We suggest that the transcriptional process influenced by a dysfunction of hepatic nuclear receptors as well as the effect of NO on the post-transcriptional process due to intestinal injury are partially involved in the down-regulation of hepatic transporters.
authors: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chūō-ku, Chiba 260-8675, Japan.
authors: Nobuhiro
authors: N
authors: Fujiyama
authors: Yoshihisa
authors: Y
authors: Shitara
authors: Toshiharu
authors: T
authors: Horie
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D015536:Down-Regulation / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology; D007213:Indomethacin / Q000009:adverse effects*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000097:blood; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3
chemical_list: D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D006146:Guanidines; D029362:Organic Anion Transporters, Sodium-Independent; D020011:Protective Agents; C421102:Slco1a1 protein, rat; C421207:Slco1b2 protein, rat; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D009569:Nitric Oxide; D000527:Alprostadil; D005978:Glutathione; C045125:ornoprostil; C004479:pimagedine; D007213:Indomethacin