GLYCOGENESIS FROM GLUCOSE AND UREAGENESIS IN ISOLATED-PERFUSED RAT LIVERS - INFLUENCE OF AMMONIUM ION, NORVALINE, AND ETHOXYZOLAMIDE

The probable involvement of hepatic carbamyl-P in the reciprocal relat ionship between hepatic ureagenesis and glycogenesis from glucose was explored. Isolated perfused liver preparations from 48-h fasted rats w ere employed. Moderate (9.2 mM) and relatively high levels of glucose (34 mM) were perfused. Hepatic glycogenesis, glucose-6-P, carbamyl-P a nd citrulline levels, hepatic urea formation, and ureagenesis based up on perfusate urea levels were measured. Experimental probes selected t o modify hepatic ureagenesis and carbamyl-P production and utilization included: (a) NH4Cl, maintained at 5 mM by continuous infusion (NH4is a substrate for carbamyl-P synthase I and glutamate dehydrogenase); (b) norvaline, an inhibitor of ornithine transcarbamylase which catal yzes the first committed step in the urea cycle; and (c) ethoxyzolamid e, an inhibitor of carbonic anhydrase which produces HCO3-, an essenti al substrate for carbamyl-P synthase I. NH4+ increased ureagenesis and decreased glycogenesis. The inclusion of norvaline with NH4+ decrease d ureagenesis and increased glycogenesis. Ethoxyzolamide with or witho ut NH4+ inhibited both ureagenesis and glycogenesis, and decreased the hepatic glucose-6-P level. Glycogenesis was greater at 34 mM than 9.2 mM glucose, increased in norvaline-containing preparations correlativ e with increased availability of carbamyl-P, and decreased when carbam yl-P formation was inhibited by ethoxyzolamide. Kinetic analysis indic ated a K-m,K- Glc Of 31 mM for glucose phosphorylation preliminary to glycogenesis. Glycogen formation via the ''indirect pathway'' (i.e. in volving extrahepatic glycolysis, transport of lactate to the liver, an d glyconeogenesis therefrom) was quantitatively insufficient to accoun t for the observed glycogenesis. Glucokinase is contraindicated by the inverse relationship between hepatic glycogenesis and ATP availabilit y in the ethoxyzolamide-treated preparations. In contrast, carbamyl-P: glucose phosphotransferase activity of the glucose-6-phosphatase syste m has the characteristics to bridge hepatic ureagenesis and glycogenes is.