Benzoate stimulates glutamate release from perfused rat liver.
In isolated perfused rat liver, benzoate addition to the influent perfusate led to a dose-dependent, rapid and reversible stimulation of glutamate output from the liver. This was accompanied by a decrease in glutamate and 2-oxoglutarate tissue levels and a net K+ release from the liver; withdrawal of benzoate was followed by re-uptake of K+. Benzoate-induced glutamate efflux from the liver was not dependent on the concentration (0-1 mM) of ammonia (NH3 + NH4+) in the influent perfusate, but was significantly increased after inhibition of glutamine synthetase by methionine sulphoximine or during the metabolism of added glutamine (5 mM). Maximal rates of benzoate-stimulated glutamate efflux were 0.8-0.9 mumol/min per g, and the effect of benzoate was half-maximal (K0.5) at 0.8 mM. Similar Vmax. values of glutamate efflux were obtained with 4-methyl-2-oxopentanoate, ketomethionine (4-methylthio-2-oxobutyrate) and phenylpyruvate; their respective K0.5 values were 1.2 mM, 3.0 mM and 3.8 mM. Benzoate decreased hepatic net ammonia uptake and synthesis of both urea and glutamine from added NH4Cl. Accordingly, the benzoate-induced shift of detoxication from urea and glutamine synthesis to glutamate formation and release was accompanied by a decreased hepatic ammonia uptake. The data show that benzoate exerts profound effects on hepatic glutamate and ammonia metabolism, providing a new insight into benzoate action in the treatment of hyperammonaemic syndromes.
Häussinger
D
D
Medizinische Universitätsklinik, Freiburg, Germany.
Stehle
T
T
Colombo
J P
JP
D000643:Ammonium Chloride / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D005974:Glutamate-Ammonia Ligase / Q000037:antagonists & inhibitors; D005971:Glutamates / Q000378:metabolism*; D005973:Glutamine / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008717:Methionine Sulfoximine / Q000494:pharmacology; D008954:Models, Biological; D010477:Perfusion; D011188:Potassium / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D001565:Benzoates; D005971:Glutamates; D000643:Ammonium Chloride; D005973:Glutamine; D008717:Methionine Sulfoximine; D005974:Glutamate-Ammonia Ligase; D011188:Potassium