title: Interaction of ibuprofen and other structurally related NSAIDs with the sodium-coupled monocarboxylate transporter SMCT1 (SLC5A8).
abstract: OBJECTIVE
  Sodium-coupled monocarboxylate transporter 1 (SMCT1) is a Na+-coupled transporter for monocarboxylates. Many nonsteroidal anti-inflammatory drugs (NSAIDs) are monocarboxylates. Therefore, we investigated the interaction of these drugs with human SMCT1 (hSMCT1).
  
  
  METHODS
  We expressed hSMCT1 in a mammalian cell line and in Xenopus laevis oocytes and used the uptake of nicotinate and propionate-induced currents to monitor its transport function, respectively. We also used [14C]-nicotinate and [3H]-ibuprofen for direct measurements of uptake in oocytes.
  
  
  RESULTS
  In mammalian cells, hSMCT1-mediated nicotinate uptake was inhibited by ibuprofen and other structurally related NSAIDs. The inhibition was Na+ dependent. With ibuprofen, the concentration necessary for 50% inhibition was 64 +/- 16 microM. In oocytes, the transport function of hSMCT1 was associated with inward currents in the presence of propionate. Under identical conditions, ibuprofen and other structurally related NSAIDs failed to induce inward currents. However, these compounds blocked propionate-induced currents. With ibuprofen, the blockade was dose dependent, Na+ dependent, and competitive. However, there was no uptake of [3H]-ibuprofen into oocytes expressing hSMCT1, although the uptake of [14C]-nicotinate was demonstrable under identical conditions.
  
  
  CONCLUSIONS
  Ibuprofen and other structurally related NSAIDs interact with hSMCT1 as blockers of its transport function rather than as its transportable substrates.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia 30912, USA.
authors.forename: Shirou
authors.initials: S
authors.lastname: Itagaki
authors.forename: Elangovan
authors.initials: E
authors.lastname: Gopal
authors.forename: Lina
authors.initials: L
authors.lastname: Zhuang
authors.forename: You-Jun
authors.initials: YJ
authors.lastname: Fei
authors.forename: Seiji
authors.initials: S
authors.lastname: Miyauchi
authors.forename: Puttur D
authors.initials: PD
authors.lastname: Prasad
authors.forename: Vadivel
authors.initials: V
authors.lastname: Ganapathy
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005279:Fenoprofen / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007052:Ibuprofen / Q000737:chemistry / Q000494:pharmacology*; D008564:Membrane Potentials; D015394:Molecular Structure; D027501:Monocarboxylic Acid Transporters; D009525:Niacin / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D011422:Propionates; D012964:Sodium / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection; D014982:Xenopus laevis
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D027682:Cation Transport Proteins; D027501:Monocarboxylic Acid Transporters; D011422:Propionates; C476760:SLC5A8 protein, human; D009525:Niacin; D012964:Sodium; D005279:Fenoprofen; D007052:Ibuprofen