BIOTRANSFORMATION OF COUMARIN DERIVATIVES (1) 7-ALKOXYCOUMARIN O-DEALKYLASE IN LIVER MICROSOMES
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概要
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The <I>in vitro</I> metabolic fate of 7-alkoxycoumarin was studied using liver microsomes. Microsomal enzyme catalyzed dealkylation of 7-alkoxycoumarin to 7-hydroxycoumarin in the presence of NADPH and molecular oxygen as cofactors was found to be one of the metabolic pathways. The metabolite 7-hydroxycoumarin was further metabolized to unidentified metabolite(s) in the presence of NADPH and O<SUB>2</SUB> at a very slow rate, while the formation of the conjugate of 7-hydroxycoumarin with glucuronic acid was observed in the presence of UDPGA. Microsomal 7-alkoxycoumarin O-dealkylase activity was altered by the substitution of the alkyl group of the substrate, and the substitutions to either an O-propyl or an O-butyl group resulted in a decrease of the enzyme activity. Species differences were observed in the substrate specificity of microsomal O-dealkylation. The O-dealkylase activities in rat liver microsomes were stimulated by pretreatment of the animals with phenobarbital, regardless of the O-alkyl substituent at the 7 position of the coumarin ring. On the other hand, pretreatment with 3-methylcholanthrene or β-naphthoflavone resulted in marked increase of O-deethylation, O-depropylation and O-debutylation activities, but not of O-demethylation activity. Pretreatment of animals with β-naphthoflavone also resulted in remarkable stimulation of 7-hydroxycoumarin-glucuronide formation by the microsomal enzyme, while the conversion of 7-hydroxycoumarin to unidentified metabolite(s) was activated by the pretreatment of rats with only phenobarbital. The O-dealkylation activities in liver microsomes from intact and phenobarbital pretreated rats were inhibited markedly by the addition of hexobarbital to the incubation mixture, but no inhibition was observed with α-naphthoflavone. On the other hand, the O-dealkylation activities in microsomes from β-naphthoflavone-pretreated rats were inhibited remarkably by α-naphtho-flavone. These results confirmed that several microsomal enzymes, including the cytochrome P-450s and UDP-glucuronyltransferase, participate in the biotransformation of 7-alkoxycoumarin, and these enzymes are regulated differently by inducers.
- 社団法人 日本薬理学会の論文
著者
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Iwata Tsuyoshi
Shionogi Research Laboratories Shionogi & Co. Ltd.
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YOSHIHARA Emiko
Shionogi Research Laboratories, Shionogi & Co., Ltd.
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Matsubara Takashi
Shionogi Research Laboratories
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HACHINO Yoshimi
Department of Pharmacy, Osaka National Hospital, Hoenzaka-machi
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TOCHINO Yoshihiro
Shionogi Research Laboratories, Shionogi & Co. Ltd.
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Yoshihara Emiko
Shionogi Research Laboratories
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IWATA Tsuyoshi
Shionogi Research Laboratories, Shionogi & Co. Ltd.
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HACHINO Yoshimi
Department of Molecular Physiological Chemistry, Medical School of Osaka University
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