title: Human organic anion transporter 2 is an entecavir, but not tenofovir, transporter.
abstract: Entecavir (ETV) and tenofovir (TFV) are essential nucleoside analogues in current hepatitis B virus (HBV) treatments. Since these drugs target the HBV polymerase that is localized within human hepatocytes, determining of their cellular uptake process is an important step in fully understanding their pharmacological actions. However, the human hepatic transporters responsible for their uptake have remained unidentified. Therefore, this study aimed at identifying the primary ETV and TFV uptake transporter(s) in human hepatocytes. In transport assays, temperature-sensitive ETV and TFV uptake by human hepatocytes were observed, and their uptake were strongly inhibited by bromosulfophthalein, which is an inhibitor of organic anion transporters/organic anion transporting polypeptides (OATs/OATPs). Given these results, ETV and TFV uptake activities in several human OAT/OATP expression systems were examined. The results showed that, among the transporters tested, only OAT2 possessed ETV transport activity. On the other hand, none of the transporters showed any TFV uptake activity. To summarize, our results identify that human OAT2 is an ETV transporter, thereby suggesting that it plays an important part in the mechanisms underlying ETV antiviral activity. Furthermore, although the hepatic TFV transporters remain unknown, our results have, at least, clarified that these two anti-HBV drugs have different hepatocyte entry routes.
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8675, Japan; Department of Pharmacology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8670, Japan. Electronic address: tomomif@faculty.chiba-u.jp.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Furihata
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8675, Japan.
authors.forename: Hanae
authors.initials: H
authors.lastname: Morio
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8675, Japan.
authors.forename: Meiyan
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8675, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8675, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Ide
authors.affiliation: Core Research Facilities for Basic Science, Division of Molecular Cell Biology, Research Center for Medical Science, The Jikei University School of Medicine, 3-19-18 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Akihito
authors.initials: A
authors.lastname: Tsubota
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8675, Japan.
authors.forename: Zhongguo
authors.initials: Z
authors.lastname: Fu
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8670, Japan.
authors.forename: Naohiko
authors.initials: N
authors.lastname: Anzai
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8675, Japan.
authors.forename: Kan
authors.initials: K
authors.lastname: Chiba
mesh_terms: D001692:Biological Transport / Q000187:drug effects; D006147:Guanine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000493:pharmacokinetics; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D013448:Sulfobromophthalein / Q000494:pharmacology; D013696:Temperature; D000068698:Tenofovir / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D029362:Organic Anion Transporters, Sodium-Independent; C490280:SLC22A7 protein, human; D013448:Sulfobromophthalein; C413685:entecavir; D006147:Guanine; D000068698:Tenofovir
keywords: Entecavir; Hepatitis B; Human hepatocytes; Organic anion transporter; Tenofovir