METABOLIC PATHWAY OF L-3-METHOXY-4-HYDROXYPHENYLALANINE (3-O-METHYL DOPA)-PARTICIPATION OF TYROSINE AMINOTRANSFERASE, AROMATIC α-KETO ACID REDUCTASE AND LACTATEDEHYDROGENASE
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概要
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The metabolic pathway of L-3-methoxy-4-hydroxyphenylalanine (3-O-methylDOPA) in the rat was investigated in vivo and in vitro. When 3-O-methylDOPA-^<14>C was incubated with rat liver homogenate, 3-methoxy-4-hydroxyphenylpyruvic acid (MHPP) was detected as the major metabolite, on addition of sodium α-ketoglutarate. Without α-ketoglutarate. 3-O-methylDOPA remained unchanged, indicating that the transamination between 3-O-methylDOPA and α-ketoglutarate is the first step in the metabolism of 3-O-methylDOPA. The enzyme responsible for the transamination was identified as tyrosine aminotransferase. After oral administration of MHPP-2-^<14>C to rats, 3-methoxy-4-hydroxyphenyllactic acid (MHPL) and homovanillic acid (HVA) (the major urinary metabolites of 3-O-methylDOPA) were detected as the major metabolites. Using rat liver homogenate, it was revealed that MHPP-2-^<14>C is transformed to MHPL with NADH but not with NADPH. Lactate dehydrogenase (LDH) was obtained from rat liver and MHPP was shown to be a substrate of LDH. It was recognized, however, that there is another dominant enzyme reducing MHPP to MHPL. This enzyme was purified from rat liver and identified as aromatic α-keto acid reductase (AKAR). Inhibition of sodium oxamate was over 95% against LDH and below 10% against AKAR, respectively, using MHPP as a substrate. Utilizing this differential inhibition of oxamate, the relative contribution of the two enzymes to the formation of MHPL from MHPP was estimated in rat tissues as 1.2-15.7% for LDH and 84.3-98.8% for AKAR, respectively.
- 公益社団法人日本薬学会の論文
著者
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SHINDO HIDEYO
Central Research Laboratories, Sankyo Co., Ltd.
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Maeda Toshihiko
Central Research Laboratories Sankyo Co. Ltd.
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Shindo Hideyo
Central Research Laboratories Sankyo Co. Ltd.
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TANAKA KAZUYO
Central Research Laboratories, Sankyo Co., Ltd.
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TANAKA Minoru
Central Research Laboratories, Sankyo Co., Ltd.
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Tanaka Kazuyo
Central Research Laboratories Sankyo Co. Ltd.
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Tanaka Minoru
Central Research Laboratories Sankyo Co. Ltd.
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- METABOLIC PATHWAY OF L-3-METHOXY-4-HYDROXYPHENYLALANINE (3-O-METHYL DOPA)-PARTICIPATION OF TYROSINE AMINOTRANSFERASE, AROMATIC α-KETO ACID REDUCTASE AND LACTATEDEHYDROGENASE