title: Involvement of functional groups on the surface of carboxyl group-terminated polyamidoamine dendrimers bearing arbutin in inhibition of Na⁺/glucose cotransporter 1 (SGLT1)-mediated D-glucose uptake.
abstract: A carboxyl group-terminated polyamidoamine dendrimer (generation: 3.0) bearing arbutin, which is a substrate of Na⁺/glucose cotransporter 1 (SGLT1), via a nonbiodegradable ω-amino triethylene glycol linker (PAMAM-ARB), inhibits SGLT1-mediated D-glucose uptake, as does phloridzin, which is a typical SGLT1 inhibitor. Here, since our previous research revealed that the activity of arbutin was dramatically improved through conjugation with the dendrimer, we examined the involvement of functional groups on the dendrimer surface in inhibition of SGLT1-mediated D-glucose uptake. PAMAM-ARB, with a 6.25% arbutin content, inhibited in vitro D-glucose uptake most strongly; the inhibitory effect decreased as the arbutin content increased. In vitro experiments using arbutin-free original dendrimers indicated that dendrimer-derived carboxyl groups actively participated in SGLT1 inhibition. However, the inhibitory effect was much less than that of PAMAM-ARB and was equal to that of glucose moiety-free PAMAM-ARB. Data supported that the glucose moiety of arbutin was essential for the high activity of PAMAM-ARB in SGLT1 inhibition. Analysis of the balance of each domain further suggested that carboxyl groups anchored PAMAM-ARB to SGLT1, and the subsequent binding of arbutin-derived glucose moieties to the target sites on SGLT1 resulted in strong inhibition of SGLT1-mediated D-glucose uptake.
authors.affiliation: Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan. sakuma@pharm.setsunan.ac.jp
authors.forename: Shinji
authors.initials: S
authors.lastname: Sakuma
authors.forename: Shun
authors.initials: S
authors.lastname: Kanamitsu
authors.forename: Yumi
authors.initials: Y
authors.lastname: Teraoka
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Masaoka
authors.forename: Makoto
authors.initials: M
authors.lastname: Kataoka
authors.forename: Shinji
authors.initials: S
authors.lastname: Yamashita
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Shirasaka
authors.forename: Ikumi
authors.initials: I
authors.lastname: Tamai
authors.forename: Masahiro
authors.initials: M
authors.lastname: Muraoka
authors.forename: Yohji
authors.initials: Y
authors.lastname: Nakatsuji
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kida
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Akashi
mesh_terms: D001104:Arbutin / Q000737:chemistry*; D001692:Biological Transport / Q000187:drug effects; D050091:Dendrimers / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D011073:Polyamines / Q000737:chemistry*; D051269:Sodium-Glucose Transporter 1 / Q000378:metabolism*
chemical_list: D050091:Dendrimers; C531249:Poly(amidoamine); D011073:Polyamines; D051269:Sodium-Glucose Transporter 1; D001104:Arbutin; D005947:Glucose