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Regulation of urea synthesis in rat liver. Inhibition of urea synthesis by L-norvaline.

The mechanism of inhibition of urea synthesis by L-norvaline was investigated in vitro with perfused rat liver and purified enzymes of the urea cycle, and in vivo. L-Norvaline caused potent inhibition of urea synthesis from ammonium chloride in the perfused liver and increases in citrulline and arginine in the liver. The increased ratio of the concentration of arginine to ornithine suggested that the main inhibition step of the urea cycle with L-norvaline is arginase. Kinetic studies with purified enzymes showed that L-norvaline inhibits arginase as well as ornithine transcarbamylase and argininosuccinate synthetase competitively with respect to their amino acid substrates, arginine, ornithine, and citrulline, respectively. The inhibition of arginase by L-norvaline was much stronger at pH 7.5 than at pH 9.7. An in vivo experiment was performed to determine whether the same inhibition mechanism operates in the rat. Judging from a decrease in urea and an increase in ammonia in the liver, intraperitoneal injection of L-norvaline caused inhibition of urea synthesis in vivo. The same conclusion, that L-norvaline inhibits urea synthesis mainly through the inhibition of arginase, was also obtained in the in vivo experiment showing an increased ratio of the concentration of arginine to ornithine. The concentration of acetylglutamate was increased by the addition of L-norvaline both in the perfused liver and in the liver in vivo, probably as a result of secondary effects of the increase in arginine.