In Vitro Inhibitory Effects of Polymethoxyflavonoids Nobiletin and Tangeretin on the Activity of Hepatic Phase-II Drug-Metabolizing Enzymes in Dams Exposed to Low-Dose 2,3,7,8-Tetrachlorodibenzo-p-dioxin

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  • INATSUGI Ryoya
    Division of Pharmaceutical Cell Biology, Faculty of Pharmaceutical Sciences, Kyushu University
  • IKEDA Kanoko
    Division of Pharmaceutical Cell Biology, Faculty of Pharmaceutical Sciences, Kyushu University
  • SANO Hiroe
    Division of Pharmaceutical Cell Biology, Graduate School of Pharmaceutical Sciences, Kyushu University
  • TSUTSUMI Ryota
    Division of Pharmaceutical Cell Biology, Graduate School of Pharmaceutical Sciences, Kyushu University
  • OHTA Chiho
    Faculty of Nutritional Sciences, Nakamura Gakuen University
  • KOGA Nobuyuki
    Faculty of Nutritional Sciences, Nakamura Gakuen University
  • TANAKA Yoshitaka
    Division of Pharmaceutical Cell Biology, Graduate School of Pharmaceutical Sciences, Kyushu University
  • ISHII Yuji
    Division of Pharmaceutical Cell Biology, Graduate School of Pharmaceutical Sciences, Kyushu University

Bibliographic Information

Other Title
  • ダイオキシン低用量暴露母体の肝薬物代謝第二相酵素活性の変動とポリメトキシフラボノイドのin vitro阻害効果
  • ダイオキシン テイヨウリョウ バクロ ボタイ ノ カン ヤクブツ タイシャ ダイニソウ コウソ カッセイ ノ ヘンドウ ト ポリメトキシフラボノイド ノ in vitro ソガイ コウカ

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Description

The present study investigated the effects of polymethoxyflavonoids nobiletin and tangeretin on uridine diphosphate-glucuronosyltransferase (UGT) activity in the livers of dams exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Pregnant Wistar rats received TCDD (1 m g/kg, p.o.) on gestational day (GD) 15, and the hepatic UGT activity and its inducibility using TCDD were assessed at GD20. UGT activity against p-nitrophenol, 4-methylumbelliferone, and SN-38 was significantly induced in hepatic S9 of TCDD-treated rats. Therefore, UGT isoforms involved in the glucuronidation of these substrates are considered TCDD-inducible in pregnant rats. Kinetic analyses were performed for pooled S9 of rats maternally exposed to TCDD and for control rats for SN-38 glucuronidation. Their Km values were comparable, but the Vmax value in TCDD group was greater than that in the control group. Considering the Km value, SN-38 concentration was fixed at 10 m M, and the inhibitory effects of nobiletin and tangeretin were studied. Nobiletin and tangeretin significantly inhibited SN-38 glucuronidation in pooled hepatic S9 in the control rats at 10 m M. Tangeretin also inhibited SN-38 glucuronidation in the TCDD-treated dams at 10 m M, whereas Nobiletin was inclined to inhibit it. At 100 m M, nobiletin and tangeretin inhibited SN-38 glucuronidation in TCDD and control groups. Although their inhibitory properties were similar, tangeretin was slightly stronger than nobiletin. Thus, UGTs are involved in hormone homeostasis. Further analysis is required to determine whether nobiletin and tangeretin reduce the adverse effects of maternal exposure to TCDD via their modulation of TCDD-induced UGT activity.

Journal

  • 福岡醫學雜誌

    福岡醫學雜誌 114 (1), 65-77, 2023-03-25

    Fukuoka Medical Association

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