The serum concentration of 7‐aminobutyric acid (GABA) has been found to be elevated by more than an order of magnitude in a rabbit model of acute hepatic failure. A potential mechanism for increased serum GABA levels in liver failure is decreased catabolism of GABA. To study this possibility, GABA‐transaminase activities were measured in nonneural tissues, and the kinetics of 3H‐GABA in vivo were defined in both normal rabbits and rabbits with galactosamine‐induced acute liver failure. Liver failure was associated with 56 and 80% increases in the activities of GABA‐transaminase in liver and kidney, respectively. In the normal rabbit following the intravenous injection of 3H‐GABA, total radioactivity in the serum decreased very rapidly initially and much more slowly after 3 to 4 min. Levels of labeled metabolites of 3H‐GABA increased very rapidly in serum and reached a plateau after 5 to 10 min. The dependence of total serum radioactivity on time was similar for rabbits 10 hr after galactosamine injection, and control rabbits, with the exception that total serum radioactivity was higher during the first 3 min of the study in galactosamine‐treated rabbits. In rabbits in hepatic coma, total serum radioactivity was higher but radioactivity in metabolites was lower than in controls at corresponding times. Clearance of 3H‐GABA from the circulation (i.e., the product of the initial volume of distribution and the fractional catabolic rate, milliliters per minute) was reduced by 26% in rabbits 10 hr after galactosamine injection and by 61% in rabbits in hepatic coma. The reduction in clearance of 3H‐GABA was associated with a decrease in the initial volume of distribution but no appreciable change in the fractional catabolic rate of GABA. The magnitude of the decrease in clearance did not fully account for the increase in serum GABA concentrations observed during acute liver failure. These findings suggest that, in addition to impaired GABA metabolism, an increase in the delivery rate of GABA to the circulation occurs in acute hepatic failure. Possible mechanisms for the latter phenomenon include increases in synthesis of GABA from glutamate in the liver and/or kidney, synthesis of GABA by gut bacteria permeability of the intestine and brain to GABA.
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