Glutamine metabolism in rat hepatocytes. Stimulation by a nonmetabolizable analog of leucine.
The metabolic effects of beta-(+/-)-2-aminobicyclo-(2.2.1)-heptane-2-carboxylic acid (BCH), a nonmetabolizable analog of leucine and known activator of glutamate dehydrogenase, were studied in hepatocytes isolated from fed and fasted rats. With glutamine as substrate, BCH stimulated in a concentration-dependent manner urea synthesis in both physiological states and glucose formation in hepatocytes from fasted rats. Despite the much higher rates of ureagenesis in the fasted animals, the degree of stimulation by BCH, over 2-fold, was similar. The effect of the drug was specific for glutamine since the rates of urea synthesis from NH4Cl, alanine, and asparagine were essentially unaltered. The stimulation of glutamine catabolism by BCH led to a decrease in the content of intracellular glutamine. The redox states of the mitochondrial and cytosolic nicotinamide adenine dinucleotides remained unaltered. In hepatocytes isolated from fasted rats and incubated with 5 mM glutamine the BCH-induced increases in urea, ammonia, and the amino acids, glutamate, aspartate, and alanine, accounted fully for the 2.4-fold rise in glutamine utilization. The stimulatory effects of BCH and glucagon on the formation of glucose, urea, and 14CO2 from [U-14C]glutamine were additive. Aminooxyacetate, and inhibitor of transaminases, neither blocked glutamine catabolism (as measured by the sum of urea, ammonia, and glutamate) nor prevented its activation by BCH. It is suggested that, in isolated hepatocytes, BCH-induced stimulation of glucose and urea formation from glutamine results from activation of glutaminase by a mechanism which is distinct from that of glucagon.
D020155:3-Hydroxybutyric Acid; D000090:Acetoacetates / Q000378:metabolism; D000596:Amino Acids / Q000494:pharmacology; D000598:Amino Acids, Cyclic; D000818:Animals; D005934:Glucagon / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism*; D006885:Hydroxybutyrates / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism; D007930:Leucine / Q000031:analogs & derivatives* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008293:Malates / Q000378:metabolism; D009952:Ornithine / Q000378:metabolism; D011773:Pyruvates / Q000378:metabolism; D019289:Pyruvic Acid; D051381:Rats; D011919:Rats, Inbred Strains; D014508:Urea / Q000096:biosynthesis
D000090:Acetoacetates; D000596:Amino Acids; D000598:Amino Acids, Cyclic; D006885:Hydroxybutyrates; D007656:Ketoglutaric Acids; D008293:Malates; D011773:Pyruvates; D005973:Glutamine; C006504:2-aminobicyclo(2,2,1)heptane-2-carboxylic acid; C016635:acetoacetic acid; C030298:malic acid; D019289:Pyruvic Acid; D014508:Urea; D005934:Glucagon; D009952:Ornithine; D007930:Leucine; D020155:3-Hydroxybutyric Acid