Influence of lysine on urea cycle activity and orotate formation in the isolated perfused rat liver

There was a reversible inhibition of urea formation in the perfused rat liver caused by 2.25-27 mM lysine acting with a Ki of 10.8 mM in competition with ornithine. Urea formation in the presence of inhibitory concentrations of lysine ranged between 2.3 and 2.9 mumol X min-1 X (g, liver wet)-1 after addition of 1 mM of citrulline, argininosuccinate or arginine, whereas it amounted to 0.5 mumol X min-1 X (g, liver wet)-1 after addition of ornithine, showing that lysine inhibited the urea cycle between ornithine and citrulline. There was a rise of basal orotate formation of 0.03 +/- 0.02 mumol X h-1 X (g, liver wet)-1 towards a maximum of 0.6 +/- 0.04 mumol X h-1 X (g, liver wet)-1 after addition of 13.5 mM lysine, provided orotate utilization was blocked with allopurinol. Maximal rates of orotate formation were reached when ammonium concentrations exceeded 1 mM. We conclude that an inhibition of urea synthesis and a rise of orotate formation are caused by lysine in the isolated liver in vitro at rates observed in vivo. Hence, these metabolic alterations observed in the whole animal are most probably due to changes of liver metabolism.