TY - JOUR
T1 - pH-dependent transport kinetics of the human organic anion-transporting polypeptide 1A2
AU - Morita, Tokio
AU - Akiyoshi, Takeshi
AU - Sato, Ryo
AU - Katayama, Kazuhiro
AU - Yajima, Kodai
AU - Kataoka, Hiroki
AU - Imaoka, Ayuko
AU - Sugimoto, Yoshikazu
AU - Ohtani, Hisakazu
N1 - Funding Information:
This work was supported in par by the Japan Research Foundation for JSPS Kakehi Grant Number 19K07173 [to T, A] and 18K06758 [to H, O].
Funding Information:
This work was supported in par by the Japan Research Foundation for JSPS Kakehi Grant Number 19K07173 [to T, A] and 18K06758 [to H, O].
Publisher Copyright:
© 2019 The Japanese Society for the Study of Xenobiotics
PY - 2020/4
Y1 - 2020/4
N2 - Organic anion-transporting polypeptide (OATP) 1A2 is expressed on the apical sides of intestinal and renal epithelial cells and considered to be involved in the intestinal absorption and renal reabsorption of drugs. Although the transport activity of OATP1A2 is considered to be pH-dependent, the effects of pH on its kinetic parameters and on the potency of OATP1A2 inhibitors are yet to be elucidated. Some OATP are known to have multiple binding sites (MBS), but it remains unclear whether OATP1A2 has MBS. In the present study, we evaluated the influence of pH on the OATP1A2-mediated uptake of estrone 3-sulfate using OATP1A2-expressing HEK293 cells. The uptake of 0.3 μM estrone 3-sulfate by HEK293-OATP1A2 cells was pH-dependent. OATP1A2 exhibited bimodal saturation kinetics at pH 6.3 and 7.4. Compared with that seen at pH 6.3 (5.62 μM), the Km value of the high-affinity site was 8-fold higher at pH 7.4 (43.2 μM). In addition, the influence of pH on the potency of inhibitors varied among the examined inhibitors. These results suggest that the transport properties of OATP1A2 under lower pH conditions, such as those found in the microenvironments of the small intestinal mucosa and distal tubules, differ from those seen under neutral pH conditions.
AB - Organic anion-transporting polypeptide (OATP) 1A2 is expressed on the apical sides of intestinal and renal epithelial cells and considered to be involved in the intestinal absorption and renal reabsorption of drugs. Although the transport activity of OATP1A2 is considered to be pH-dependent, the effects of pH on its kinetic parameters and on the potency of OATP1A2 inhibitors are yet to be elucidated. Some OATP are known to have multiple binding sites (MBS), but it remains unclear whether OATP1A2 has MBS. In the present study, we evaluated the influence of pH on the OATP1A2-mediated uptake of estrone 3-sulfate using OATP1A2-expressing HEK293 cells. The uptake of 0.3 μM estrone 3-sulfate by HEK293-OATP1A2 cells was pH-dependent. OATP1A2 exhibited bimodal saturation kinetics at pH 6.3 and 7.4. Compared with that seen at pH 6.3 (5.62 μM), the Km value of the high-affinity site was 8-fold higher at pH 7.4 (43.2 μM). In addition, the influence of pH on the potency of inhibitors varied among the examined inhibitors. These results suggest that the transport properties of OATP1A2 under lower pH conditions, such as those found in the microenvironments of the small intestinal mucosa and distal tubules, differ from those seen under neutral pH conditions.
KW - Multiple binding site
KW - OATP1A2
KW - Uptake transporter
KW - pH-dependency
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U2 - 10.1016/j.dmpk.2019.12.002
DO - 10.1016/j.dmpk.2019.12.002
M3 - Article
C2 - 31974044
AN - SCOPUS:85077984419
SN - 1347-4367
VL - 35
SP - 220
EP - 227
JO - Drug Metabolism and Pharmacokinetics
JF - Drug Metabolism and Pharmacokinetics
IS - 2
ER -