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Research ArticleArticle

Functional Investigation of Solute Carrier Family 35, Member F2, in Three Cellular Models of the Primate Blood-Brain Barrier

Tatsuki Mochizuki, Tadahaya Mizuno, Toshiki Kurosawa, Tomoko Yamaguchi, Kei Higuchi, Yuma Tega, Yoshitane Nozaki, Kenji Kawabata, Yoshiharu Deguchi and Hiroyuki Kusuhara
Drug Metabolism and Disposition January 2021, 49 (1) 3-11; DOI: https://doi.org/10.1124/dmd.120.000115
Tatsuki Mochizuki
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (T.Mo., T.Mi., H.K.); Laboratory of Drug Disposition and Pharmacokinetics, Faculty of Pharma-Sciences, Teikyo University, Tokyo, Japan (T.K., K.H., Y.T., Y.D.); Laboratory of Stem Cell Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan (T.Y., K.K.); and Drug Metabolism and Pharmacokinetics Tsukuba, Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Ibaraki, Japan (Y.N.)
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Tadahaya Mizuno
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (T.Mo., T.Mi., H.K.); Laboratory of Drug Disposition and Pharmacokinetics, Faculty of Pharma-Sciences, Teikyo University, Tokyo, Japan (T.K., K.H., Y.T., Y.D.); Laboratory of Stem Cell Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan (T.Y., K.K.); and Drug Metabolism and Pharmacokinetics Tsukuba, Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Ibaraki, Japan (Y.N.)
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  • ORCID record for Tadahaya Mizuno
Toshiki Kurosawa
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (T.Mo., T.Mi., H.K.); Laboratory of Drug Disposition and Pharmacokinetics, Faculty of Pharma-Sciences, Teikyo University, Tokyo, Japan (T.K., K.H., Y.T., Y.D.); Laboratory of Stem Cell Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan (T.Y., K.K.); and Drug Metabolism and Pharmacokinetics Tsukuba, Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Ibaraki, Japan (Y.N.)
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Tomoko Yamaguchi
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (T.Mo., T.Mi., H.K.); Laboratory of Drug Disposition and Pharmacokinetics, Faculty of Pharma-Sciences, Teikyo University, Tokyo, Japan (T.K., K.H., Y.T., Y.D.); Laboratory of Stem Cell Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan (T.Y., K.K.); and Drug Metabolism and Pharmacokinetics Tsukuba, Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Ibaraki, Japan (Y.N.)
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Kei Higuchi
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (T.Mo., T.Mi., H.K.); Laboratory of Drug Disposition and Pharmacokinetics, Faculty of Pharma-Sciences, Teikyo University, Tokyo, Japan (T.K., K.H., Y.T., Y.D.); Laboratory of Stem Cell Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan (T.Y., K.K.); and Drug Metabolism and Pharmacokinetics Tsukuba, Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Ibaraki, Japan (Y.N.)
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Yuma Tega
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (T.Mo., T.Mi., H.K.); Laboratory of Drug Disposition and Pharmacokinetics, Faculty of Pharma-Sciences, Teikyo University, Tokyo, Japan (T.K., K.H., Y.T., Y.D.); Laboratory of Stem Cell Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan (T.Y., K.K.); and Drug Metabolism and Pharmacokinetics Tsukuba, Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Ibaraki, Japan (Y.N.)
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Yoshitane Nozaki
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (T.Mo., T.Mi., H.K.); Laboratory of Drug Disposition and Pharmacokinetics, Faculty of Pharma-Sciences, Teikyo University, Tokyo, Japan (T.K., K.H., Y.T., Y.D.); Laboratory of Stem Cell Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan (T.Y., K.K.); and Drug Metabolism and Pharmacokinetics Tsukuba, Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Ibaraki, Japan (Y.N.)
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Kenji Kawabata
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (T.Mo., T.Mi., H.K.); Laboratory of Drug Disposition and Pharmacokinetics, Faculty of Pharma-Sciences, Teikyo University, Tokyo, Japan (T.K., K.H., Y.T., Y.D.); Laboratory of Stem Cell Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan (T.Y., K.K.); and Drug Metabolism and Pharmacokinetics Tsukuba, Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Ibaraki, Japan (Y.N.)
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Yoshiharu Deguchi
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (T.Mo., T.Mi., H.K.); Laboratory of Drug Disposition and Pharmacokinetics, Faculty of Pharma-Sciences, Teikyo University, Tokyo, Japan (T.K., K.H., Y.T., Y.D.); Laboratory of Stem Cell Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan (T.Y., K.K.); and Drug Metabolism and Pharmacokinetics Tsukuba, Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Ibaraki, Japan (Y.N.)
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Hiroyuki Kusuhara
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (T.Mo., T.Mi., H.K.); Laboratory of Drug Disposition and Pharmacokinetics, Faculty of Pharma-Sciences, Teikyo University, Tokyo, Japan (T.K., K.H., Y.T., Y.D.); Laboratory of Stem Cell Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan (T.Y., K.K.); and Drug Metabolism and Pharmacokinetics Tsukuba, Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Ibaraki, Japan (Y.N.)
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Abstract

Understanding the mechanisms of drug transport across the blood-brain barrier (BBB) is an important issue for regulating the pharmacokinetics of drugs in the central nervous system. In this study, we focused on solute carrier family 35, member F2 (SLC35F2), whose mRNA is highly expressed in the BBB. SLC35F2 protein was enriched in isolated mouse and monkey brain capillaries relative to brain homogenates and was localized exclusively on the apical membrane of MDCKII cells and brain microvascular endothelial cells (BMECs) differentiated from human induced pluripotent stem cells (hiPS-BMECs). SLC35F2 activity was assessed using its substrate, YM155, and pharmacological experiments revealed SLC35F2 inhibitors, such as famotidine (half-maximal inhibitory concentration, 160 μM). Uptake of YM155 was decreased by famotidine or SLC35F2 knockdown in immortalized human BMECs (human cerebral microvascular endothelial cell/D3 cells). Furthermore, famotidine significantly inhibited the apical (A)-to-basal (B) transport of YM155 in primary cultured monkey BMECs and hiPS-BMECs. Crucially, SLC35F2 knockout diminished the A-to-B transport and intracellular accumulation of YM155 in hiPS-BMECs. By contrast, in studies using an in situ brain perfusion technique, neither deletion of Slc35f2 nor famotidine reduced brain uptake of YM155, even though YM155 is a substrate of mouse SLC35F2. YM155 uptake was decreased significantly by losartan and naringin, inhibitors for the organic anion transporting polypeptide (OATP) 1A4. These findings suggest SLC35F2 is a functional transporter in various cellular models of the primate BBB that delivers its substrates to the brain and that its relative importance in the BBB is modified by differences in the expression of OATPs between primates and rodents.

SIGNIFICANCE STATEMENT This study demonstrated that SLC35F2 is a functional drug influx transporter in three different cellular models of the primate blood-brain barrier (i.e., human cerebral microvascular endothelial cell/D3 cells, primary cultured monkey BMECs, and human induced pluripotent stem-BMECs) but has limited roles in mouse brain. SLC35F2 facilitates apical-to-basal transport across the tight cell monolayer. These findings will contribute to the development of improved strategies for targeting drugs to the central nervous system.

Footnotes

    • Received May 11, 2020.
    • Accepted October 8, 2020.
  • ↵1 T.Mo. and T.Mi. contributed equally to this work.

  • ↵2 Current affiliation: Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, Texas.

  • This study is supported by a Grant-in-Aid for Scientific Research (B) [Grant 26293032] and a Grant-in-Aid for Japan Society for the Promotion of Science Fellows [Grant 20J14855] from the Japan Society for the Promotion of Science.

  • The authors declare no conflict of interest.

  • https://doi.org/10.1124/dmd.120.000115.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 49 (1)
Drug Metabolism and Disposition
Vol. 49, Issue 1
1 Jan 2021
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Research ArticleArticle

Role of SLC35F2 in Various BBB Models

Tatsuki Mochizuki, Tadahaya Mizuno, Toshiki Kurosawa, Tomoko Yamaguchi, Kei Higuchi, Yuma Tega, Yoshitane Nozaki, Kenji Kawabata, Yoshiharu Deguchi and Hiroyuki Kusuhara
Drug Metabolism and Disposition January 1, 2021, 49 (1) 3-11; DOI: https://doi.org/10.1124/dmd.120.000115

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Research ArticleArticle

Role of SLC35F2 in Various BBB Models

Tatsuki Mochizuki, Tadahaya Mizuno, Toshiki Kurosawa, Tomoko Yamaguchi, Kei Higuchi, Yuma Tega, Yoshitane Nozaki, Kenji Kawabata, Yoshiharu Deguchi and Hiroyuki Kusuhara
Drug Metabolism and Disposition January 1, 2021, 49 (1) 3-11; DOI: https://doi.org/10.1124/dmd.120.000115
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