Comparative Study on Nobiletin Metabolism with Liver Microsomes from Rats, Guinea Pigs and Hamsters and Rat Cytochrome P450(Pharmacology)
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概要
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In vitro metabolism of nobiletin, a polymethoxy-flavonoid abundantly present in citrus peels, was studied using liver microsomes of rats, hamsters and guinea pigs and ten cDNA-expressed rat cytochrome P450 (P450). The effects of P450 inducers on nobiletin metabolism were also investigated. Aerobical incubation with NADPH and animal liver microsomes transformed nobiletin to five metabolites, M-1, M-2, M-3, M-4 and M-5. From LC-MS and ^1H-NMR data and a time-course study, these were assumed to be 4'-hydroxy (OH)-, 7-OH-, 6-OH-, 3', 4'-diOH- and 6, 7-diOH-metabolites, respectively. Pretreatment of animals with phenobarbital increased M-2 and M-3 to about 2-fold that in untreated animals. Pretreatment with 3-methylcholanthrene (MC) resulted in remarkable increases of both M-1 and M-4 (3 to 9-fold that of untreated). Males had 2-3 times higher M-2 and M-3 formation activities in rats, and for M-2 in hamsters than did females. Immunoinhibition study using antiserum against P450 revealed the involvement of hamster CYP1A2 in the formation of M-1 and M-4 in hamster liver. Of ten rat P450s, CYP2C11, CYP3A1, CYP3A2 and CYP2D1 had high activities for the formation of M-1, M-2 and M-3. Another P450s (CYP1A1, CYP2C12 and CYP1A2) also showed activity for the formation of M-1. Only CYP1A1 produced 3', 4'-diOH-metabolites (M-4). However, CYP2A1, CYP2B1 and CYP2E1 had no activity for nobiletin. These results suggested that constitutive P450s such as CYP2C11, CYP2D1, CYP3A1, CYP3A2 and CYP2C12 are responsible for the demethylation at the 6-, 7-, 3'- and 4'-positions; whereas, MC-inducible P450s, CYP1A1 and CYP1A2, preferentially catalyzed demethylation at the 3'-and 4'-positions.
- 社団法人日本薬学会の論文
- 2007-12-01
著者
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Ohta Hideaki
Graduate School Of Health And Nutrition Sciences Nakamura Gakuen University
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Ohta Chiho
Faculty Of Nutritional Sciences Nakamura Gakuen University
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Ohta Chiho
中村学園大学 栄養科学部
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Koga Nobuyuki
Faculty Of Pharmaceutical Sciences Kyushu University
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Koga Nobuyuki
Graduate School Of Health And Nutrition Sciences Nakamura Gakuen University
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Yano Masamichi
Department Of Citriculture National Research Institute Of Fruit Tree Science
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Kato Yoshihisa
Kagawa School Of Pharmaceutical Sciences Tokushima Bunri University
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MATSUO Miki
Faculty of Nutritional Sciences, Nakamura Gakuen University
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HARAGUCHI Koichi
Daiichi College of Pharmaceutical Sciences
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MATSUOKA Mikiko
Faculty of Nutritional Sciences, Nakamura Gakuen University
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ISHII Toshinao
Faculty of Nutritional Sciences, Nakamura Gakuen University
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YANO Masamichi
Laboratory of Postharvest Physiology, Department of Citriculture, National Institute of Fruit Tree S
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OHTA Hideaki
Faculty of Nutritional Sciences, Nakamura Gakuen University
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Ohta Hideaki
Faculty Of Nutritional Sciences Nakamura Gakuen University
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Ohta Hideaki
Faculty Of Nutritional Science Nakamura Gakuen University
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Matsuo Miki
Faculty Of Nutritional Sciences Nakamura Gakuen University
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Ohta Hideaki
Chugoku National Agricultural Experiment Station Ministry Of Agriculture Foresty And Fisheries
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Ishii Toshinao
Faculty Of Nutritional Sciences Nakamura Gakuen University
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Haraguchi Koichi
Daiichi College Of Pharmaceutical Science
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Ohta H
Graduate School Of Health And Nutrition Sciences Nakamura Gakuen University
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Koga Nobuyuki
Faculty of Nutritional Sciences, Nakamura Gakuen University
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