TY - JOUR
T1 - Comparison of the inhibitory properties of the fruit component naringenin and its glycosides against OATP1A2 genetic variants
AU - Araki, Naoya
AU - Morita, Tokio
AU - Akiyoshi, Takeshi
AU - Kataoka, Hiroki
AU - Yajima, Kodai
AU - Katayama, Kazuhiro
AU - Imaoka, Ayuko
AU - Ohtani, Hisakazu
N1 - Funding Information:
This study was supported, in part, by the Japan Research Foundation through JSPS Kakenhi grants (grant numbers 19K07173 [T.A.] and 18K06758 [H.O.]).
Publisher Copyright:
© 2022
PY - 2022/10
Y1 - 2022/10
N2 - Non-synonymous genetic variants of organic anion-transporting polypeptide (OATP) 1A2 with altered transport activity have been identified. Naringin and narirutin, which are found in grapefruit, and their aglycon naringenin inhibit OATP1A2. However, their inhibitory effects on OATP1A2 variants have not been investigated, nor has the influence of their molecular structure, such as the number of sugar moieties, on their inhibitory potency. This study aimed to investigate the inhibitory effects of naringenin, its monosaccharide glycoside prunin, and its disaccharide glycosides naringin and narirutin on fexofenadine (FEX) uptake by OATP1A2 variants (Ile13Thr, Asn128Tyr, Ala187Thr, and Thr668Ser). Naringin, narirutin, and prunin inhibited FEX (0.3 μM) uptake by all of the examined OATP1A2 variants in a concentration-dependent manner. Compared with those for the wild type, the inhibition constants (Ki) of naringin, narirutin, and prunin for the Ala187Thr variant were significantly increased by 3.36-fold, 7.55-fold, and 10.6-fold, respectively. Naringenin inhibited all of the OATP1A2 variants, except Ala187Thr, concentration-dependently. The order of inhibitory potency was as follows for all variants: aglycone > monosaccharide glycoside > disaccharide glycosides. These results suggest that the Ala187Thr variant is less vulnerable to inhibition by naringenin and its glycosides. Moreover, greater glycosylation of naringenin reduces its inhibitory potency against OATP1A2.
AB - Non-synonymous genetic variants of organic anion-transporting polypeptide (OATP) 1A2 with altered transport activity have been identified. Naringin and narirutin, which are found in grapefruit, and their aglycon naringenin inhibit OATP1A2. However, their inhibitory effects on OATP1A2 variants have not been investigated, nor has the influence of their molecular structure, such as the number of sugar moieties, on their inhibitory potency. This study aimed to investigate the inhibitory effects of naringenin, its monosaccharide glycoside prunin, and its disaccharide glycosides naringin and narirutin on fexofenadine (FEX) uptake by OATP1A2 variants (Ile13Thr, Asn128Tyr, Ala187Thr, and Thr668Ser). Naringin, narirutin, and prunin inhibited FEX (0.3 μM) uptake by all of the examined OATP1A2 variants in a concentration-dependent manner. Compared with those for the wild type, the inhibition constants (Ki) of naringin, narirutin, and prunin for the Ala187Thr variant were significantly increased by 3.36-fold, 7.55-fold, and 10.6-fold, respectively. Naringenin inhibited all of the OATP1A2 variants, except Ala187Thr, concentration-dependently. The order of inhibitory potency was as follows for all variants: aglycone > monosaccharide glycoside > disaccharide glycosides. These results suggest that the Ala187Thr variant is less vulnerable to inhibition by naringenin and its glycosides. Moreover, greater glycosylation of naringenin reduces its inhibitory potency against OATP1A2.
KW - Citrus fruits
KW - Food-drug interaction
KW - Genetic variants
KW - Naringenin
KW - Naringin
KW - Narirutin
KW - OATP1A2
KW - Prunin
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U2 - 10.1016/j.dmpk.2022.100464
DO - 10.1016/j.dmpk.2022.100464
M3 - Article
C2 - 35841754
AN - SCOPUS:85134160950
SN - 1347-4367
VL - 46
JO - Drug Metabolism And Pharmacokinetics
JF - Drug Metabolism And Pharmacokinetics
M1 - 100464
ER -