title: Prostaglandin transporter (OATP2A1/SLCO2A1) contributes to local disposition of eicosapentaenoic acid-derived PGE3.
abstract: Eicosapentaenoic acid (EPA)-derived prostaglandin E3 (PGE3) possesses an anti-inflammatory effect; however, information for transporters that regulate its peri-cellular concentration is limited. The present study, therefore, aimed to clarify transporters involved in local disposition of PGE3. PGE3 uptake was assessed in HEK293 cells transfected with OATP2A1/SLCO2A1, OATP1B1/SLCO1B1, OATP2B1/SLCO2B1, OAT1/SLC22A6, OCT1/SLC22A1 or OCT2/SLC22A2 genes, compared with HEK293 cells transfected with plasmid vector alone (Mock). PGE3 uptake by OATP2A1-expressing HEK293 cells (HEK/2A1) was the highest and followed by HEK/1B1, while no significantly higher uptake of PGE3 than Mock cells was detected by other transporters. Saturation kinetics in PGE3 uptake by HEK/2A1 estimated the Km as 7.202 ± 0.595 μM, which was 22 times higher than that of PGE2 (Km=0.331 ± 0.131 μM). Furthermore, tissue disposition of PGE3 was examined in wild-type (WT) and Slco2a1-deficient (Slco2a1(-/-)) mice after oral administration of EPA ethyl ester (EPA-E) when they underwent intraperitoneal injection of endotoxin (e.g., lipopolysaccharide). PGE3 concentration was significantly higher in the lung, and tended to increase in the colon, stomach, and kidney of Slco2a1(-/-), compared to WT mice. Ratio of PGE2 metabolite 15-keto PGE2 over PGE2 concentration was significantly lower in the lung and colon of Slco2a1(-/-) than that of WT mice, suggesting that PGE3 metabolism is downregulated in Slco2a1(-/-) mice. In conclusion, PGE3 was found to be a substrate of OATP2A1, and local disposition of PGE3 could be regulated by OATP2A1 at least in the lung.
authors.affiliation: Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Tomoka
authors.initials: T
authors.lastname: Gose
authors.affiliation: Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Nakanishi
authors.affiliation: Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kamo
authors.affiliation: Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimada
authors.affiliation: Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Katsumasa
authors.initials: K
authors.lastname: Otake
authors.affiliation: Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan. Electronic address: tamai@p.kanazawa-u.ac.jp.
authors.forename: Ikumi
authors.initials: I
authors.lastname: Tamai
mesh_terms: D000284:Administration, Oral; D000527:Alprostadil / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D001692:Biological Transport; D003106:Colon / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism / Q000493:pharmacokinetics; D015118:Eicosapentaenoic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D027381:Liver-Specific Organic Anion Transporter 1 / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D018345:Mice, Knockout; D009154:Mutation; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D014018:Tissue Distribution / Q000187:drug effects; D014162:Transfection
chemical_list: D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; C503526:SLCO2A1 protein, human; C035276:eicosapentaenoic acid ethyl ester; C033246:prostaglandin E3; D015118:Eicosapentaenoic Acid; D000527:Alprostadil; D015232:Dinoprostone
keywords: Eicosapentaenoic acid; Inflammation; Knock-out mice; OATP2A1; Prostaglandin E(3)