Characterization of alpha-keto acid transport across blood-brain barrier in rats.
The transport of keto acids, monocarboxylic acids, and ketone bodies was studied in barbiturate-anesthetized, adult male Sprague-Dawley rats. [1-14C]propionate and D-3-[3-14C]hydroxybutyrate were found to cross the blood-brain barrier with brain uptake indexes of 43.53 and 7.10%, respectively. Transport of both of these substrates was saturable, with the values of transport Km being 2.03 and 6.54 mM, respectively. A Ki of 0.68 mM was derived from competition data measuring the uptake of [1-14C]alpha-ketoisocaproate in the presence of unlabeled alpha-ketobutyrate. This finding and results from classical inhibition studies support competition for transport of keto acids for a common carrier. The brain uptake of [1-14C]propionate was significantly reduced by keto acids and ketone bodies and the transport of D-3-[3-14C]hydroxybutyrate was significantly inhibited by unlabeled monocarboxylic acids, keto acids, and acetoacetate. Evidence for competitive transport of alpha-keto acids, monocarboxylic acids, and ketone bodies is presented in the form of classical double-reciprocal inhibition plots and of labeled monocarboxylic acids and ketone bodies by an increasing concentration of unlabeled alpha-ketoisocaproate, the latter method yielding Ki values of 0.29 and 0.63 mM, respectively. The brain uptake of labeled propionate was inhibited by unlabeled D-3-hydroxybutyrate. A Ki of 6.43 mM, derived from this data, approximated the Km of transport of D-3-hydroxybutyrate, suggesting that ketone bodies and monocarboxylic acids compete for transport via the same carrier that is operative for keto acids.
D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier; D002208:Caproates / Q000378:metabolism; D002250:Carbon Radioisotopes; D007651:Keto Acids / Q000378:metabolism*; D007700:Kinetics; D007930:Leucine / Q000378:metabolism; D008297:Male; D011422:Propionates / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D002208:Caproates; D002250:Carbon Radioisotopes; D007651:Keto Acids; D011422:Propionates; C013082:alpha-ketoisocaproic acid; D007930:Leucine; C029658:propionic acid