Hepatic Na(+)-dicarboxylate cotransport: identification, characterization, and acinar localization.
Rat liver perfusion studies suggest that the transport of alpha-ketoglutarate (KG) and related dicarboxylates exhibits acinar heterogeneity, in that the uptake and subsequent metabolism of these organic anions appears to occur predominantly in the perivenous region. However, the isolated perfused liver as an experimental model cannot distinguish intra-acinar differences in either the rate of solute uptake and/or efflux or intracellular binding and/or metabolism. Therefore, the driving forces and acinar localization of KG transport were examined using rat basolateral liver plasma membrane vesicles (blLPMV) isolated from control animals and animals treated 24 h before with selective perivenous and periportal toxins [carbon tetrachloride (CCl4) and allyl alcohol (AA), respectively]. In control blLPMV, [14C]KG uptake into an osmotically sensitive space was markedly stimulated by an inwardly directed Na+ gradient but not by inwardly directed gradients of other monovalent cations. The Na+ ionophore, gramicidin, had a small but significant inhibitory effect on Na(+)-dependent KG uptake, demonstrating that KG uptake was not the result of an intravesicular positive Na+ diffusion potential. The protonophore, carbonyl cyanide-p-trifluoromethoxyphenylhydrazone, had no effect on Na+ gradient-driven KG uptake, indicating that KG uptake was not the indirect result of coordinated activities of Na-H and KG-OH exchange. Na+ gradient-driven KG uptake was electrogenic (occurring with the net transfer of positive charge), and cis-inhibited by other tricarboxylic acid cycle intermediates, including succinate, fumarate, and malate and by citrate, but not by the dicarboxylates oxalate and malonate nor by glutamate and taurocholate (TC).(ABSTRACT TRUNCATED AT 250 WORDS)
Moseley
R H
RH
Department of Internal Medicine, Veterans Affairs Medical Center, Ann Arbor, Michigan.
Jarose
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Permoad
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D000433:1-Propanol / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D002251:Carbon Tetrachloride / Q000494:pharmacology; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D002412:Cations / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D020005:Propanols; D051381:Rats; D012964:Sodium / Q000494:pharmacology; D013379:Substrate Specificity; D014018:Tissue Distribution
D002412:Cations; D007656:Ketoglutaric Acids; D020005:Propanols; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; C006463:allyl alcohol; D000433:1-Propanol; D012964:Sodium; D002251:Carbon Tetrachloride