Interactions between lithium and renal transport of Krebs cycle intermediates.

Abstract

The effect of Li [used in the treatment of manic-depressive of illness] on the renal transport of Krebs cycle intermediates was studied in brush border membrane vesicles isolated from the rabbit renal cortex. The di- and tricarboxylic acids are avidly transported across renal brush border membranes by a Na cotransport system. Li acted as a potent, specific, competitive inhibitor (Ki [inhibition constant] = 1.2 mM) of succinate/Na cotransport when added to the uptake medium. Similar effects were observed for citrate but not D-glucose, L-phenylalanine, L-proline, L-alanine or L-lactate transport. Intravesicular Li behaved as a noncompetitive inhibitor of succinate transport in the absence of Na. These results account for the observation that therapeutic doses of Li increase the renal excretion of Krebs cycle intermediates. The existence of a transport system for .alpha.-ketoglutarate in synaptosomes suggests a possible target for Li in the CNS.