title: Intestinal ischemia-reperfusion increases efflux for uric acid via paracellular route in the intestine, but decreases that via transcellular route mediated by BCRP.
abstract: OBJECTIVE
  Uric acid is thought to be one of the most important antioxidants in human biological fluids. Intestinal ischemia-reperfusion (I/R) is an important factor associated with high rates of morbidity and mortality. Reactive oxygen species (ROS) are responsible for intestinal I/R injury. The aim of this study was to clarify the efflux for uric acid from the intestine after intestinal I/R.
  
  
  METHODS
  We used intestinal ischemia-reperfusion (I/R) model rats. Serosal to mucosal flux for [¹⁴C]-uric acid was assessed by using Ussing-type diffusion chambers. BCRP/Bcrp expression was assessed by Western blot analysis. Caco-2 cells were used for a model of the intestinal epithelium, and rotenone was used as a mitochondrial dysfunction inducer.
  
  
  RESULTS
  Serosal to mucosal flux for uric acid was increased after intestinal I/R, and that for mannitol was also increased. Ko143, which is a BCRP inhibitor, did not affect the uric acid transport. The decreasing uric acid transport mediated by Bcrp was caused by decrease in the level of Bcrp homodimer, bridged by an S-S bond. The suppression of Bcrp S-S bond formation was associated with mitochondrial dysfunction. Moreover, BCRP S-S bond formation activity was decreased by rotenone in Caco-2 cells.
  
  
  CONCLUSIONS
  Serosal to mucosal flux for uric acid is significantly increased via the paracelluler route, but that via the transcellular route mediated by Bcrp is decreased after intestinal I/R. The decreasing uric acid flux mediated by Bcrp is caused by suppression of Bcrp S-S bond formation. This suppression of Bcrp S-S bond formation may be related to mitochondrial dysfunction.
authors.affiliation: Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Ogura
authors.forename: Kaori
authors.initials: K
authors.lastname: Kuwayama
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takaya
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Terada
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsujimoto
authors.forename: Takahiro
authors.initials: T
authors.lastname: Koizumi
authors.forename: Hajime
authors.initials: H
authors.lastname: Maruyama
authors.forename: Asuka
authors.initials: A
authors.lastname: Fujikawa
authors.forename: Natsuko
authors.initials: N
authors.lastname: Takahashi
authors.forename: Masaki
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Shirou
authors.initials: S
authors.lastname: Itagaki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hirano
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Ken
authors.initials: K
authors.lastname: Iseki
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D054659:Diketopiperazines; D006576:Heterocyclic Compounds, 4 or More Rings; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000293:injuries; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000378:metabolism*; D012402:Rotenone / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology; D014527:Uric Acid / Q000378:metabolism*
chemical_list: C541506:3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino(1',2'-1,6)pyrido(3,4-b)indol-3-yl)propionic acid tert-butyl ester; C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C489249:Abcg2 protein, rat; D054659:Diketopiperazines; D006576:Heterocyclic Compounds, 4 or More Rings; D009363:Neoplasm Proteins; D014475:Uncoupling Agents; D012402:Rotenone; D014527:Uric Acid; D000241:Adenosine