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Inhibition of amino acid transaminases by L-cycloserine

1973; Pergamon Press; Volume: 11; Linguagem: Inglês

10.1016/0065-2571(73)90013-7

1873-2437

David T. Wong, Ray W. Fuller, Bryan B. Molloy,

Metabolism and Genetic Disorders

1.l-Cycloserine inhibited in vitro three hepatic transaminating enzymes, alanine aminotransferase, phenylalanine aminotransferase, and tyrosine aminotransferase. The inhibition was irreversible and noncompetitive with respect to the amino-acid substrate. The D isomer of cycloserine was less effective as an inhibitor. 2.In the isolated, perfused rat liver, l-cycloserine inhibited total gluconeogenesis and the conversion of 14C-alanine to 14-C-glucose and 14C-carbon dioxide. l-cycloserine had little or no effect on gluconeogenesis from pyruvate or glutamate. 3.In rats, l-cycloserine inhibited alanine aminotransferase and phenylalanine aminotransferase in vivo as measured by enzyme assay of homogenized tissue from treated rats. Alanine aminotransferase was also inhibited in heart, brain, and kidney. The long duration of inhibition suggested irreversible enzyme inactivation. 4.In fasted rats, the conversion of 14C-alanine to expired 14C-carbon dioxide was markedly inhibited by l-cycloserine. The inhibition was dose-related and occurred at i.p. doses as low as 1 mg/kg. The conversion of 14C-glutamate to 14C-carbon dioxide was only marginally affected by a high dose (100 mg/kg) of l-cycloserine. 5.In fasted rats, the release of 3H from alanine-2-3H into plasma water was inhibited by l-cycloserine (10 mg/kg), a direct indication that alanine transamination was inhibited. 6.These results lend further evidence for the effectiveness of l-cycloserine as an inhibitor of alanine aminotransferase and demonstrate that two additional aminotransferases are also affected to a lesser degree. The use of l-cycloserine may help elucidate the significance of amino acid transamination in various physiologic states.