Down-regulation of hepatic transporters for BSP in rats with indomethacin-induced intestinal injury.
Previous reports have demonstrated that an intestinal injury causes hypofunctions of the liver associated with down-regulations of cytochrome P450, but an influence on hepatic transporters remains unclear. Here, we tested hepatic transporter functions in a rat model of bowel injury using indomethacin (IDM). After administration of IDM (8.5 mg/kg, i.p., 3 d), the rats suffered the intestinal impairment indicated by a reduction of alkaline phosphatase activity in mucosa. In vivo pharmacokinetic experiments of bromosulfophthalein (BSP) showed that there was a reduction in its plasma elimination rate and cumulative biliary excretion in IDM-treated rats and systemic and biliary clearances reduced to nearly 50% of the control group. Protein expressions in plasma membrane and mRNA levels of organic anion transporting polypeptide 1b2 (Oatp1b2) and multidrug resistance-associated protein 2 (Mrp2), which play hepatic BSP uptake and biliary excretion, respectively, in the liver were significantly reduced following the IDM treatment. In portal plasma, the levels of proinflammatory cytokines were unchanged, while the level of nitric oxide metabolites (NO2- + NO3-) increased to 6.5-fold that of the control. The time-course on IDM treatment indicated that, firstly, intestinal injury was induced, the NO level increased, and the hepatic Oatp1b2 and Mrp2 expression began to fall followed by an increase in plasma ALT. In conclusion, IDM-induced injury to the small intestine causes the hypofunction of hepatic Oatp1b2 and Mrp2 independently on the hepatic impairment, and NO arising from bowel injury may be one of key factors for it through the remote effect.
Fujiyama
Nobuhiro
N
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana Chuoku, Chiba 260-8675, Japan.
Shitara
Yoshihisa
Y
Ito
Kousei
K
Masubuchi
Yasuhiro
Y
Horie
Toshiharu
T
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001646:Bile / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D004396:Coloring Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D015536:Down-Regulation; D007077:Ileal Diseases / Q000139:chemically induced / Q000503:physiopathology; D007213:Indomethacin / Q000008:administration & dosage / Q000633:toxicity*; D018836:Inflammation Mediators / Q000097:blood; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007410:Intestinal Diseases / Q000139:chemically induced / Q000503:physiopathology*; D007579:Jejunal Diseases / Q000139:chemically induced / Q000503:physiopathology; D008099:Liver / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013448:Sulfobromophthalein / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*
D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D004396:Coloring Agents; D018836:Inflammation Mediators; D026901:Membrane Transport Proteins; D029362:Organic Anion Transporters, Sodium-Independent; D012333:RNA, Messenger; C421102:Slco1a1 protein, rat; D013448:Sulfobromophthalein; D000410:Alanine Transaminase; D007213:Indomethacin