Blood-brain barrier transport of kynurenines: implications for brain synthesis and metabolism.
To evaluate the potential contribution of circulating kynurenines to brain kynurenine pools, the rates of cerebral uptake and mechanisms of blood-brain barrier transport were determined for several kynurenine metabolites of tryptophan, including L-kynurenine (L-KYN), 3-hydroxykynurenine (3-HKYN), 3-hydroxyanthranilic acid (3-HANA), anthranilic acid (ANA), kynurenic acid (KYNA), and quinolinic acid (QUIN), in pentobarbital-anesthetized rats using an in situ brain perfusion technique. L-KYN was found to be taken up into brain at a significant rate [permeability-surface area product (PA) = 2-3 x 10(-3) ml/s/g] by the large neutral amino acid carrier (L-system) of the blood-brain barrier. Best-fit estimates of the Vmax and Km of saturable L-KYN transfer equalled 4.5 x 10(-4) mumol/s/g and 0.16 mumol/ml, respectively. The same carrier may also mediate the brain uptake of 3-HKYN as D,L-3-HKYN competitively inhibited the brain transfer of the large neutral amino acid L-leucine. For the other metabolites, uptake appeared mediated by passive diffusion. This occurred at a significant rate for ANA (PA, 0.7-1.6 x 10(-3) ml/s/g), and at far lower rates (PA, 2-7 x 10(-5) ml/s/g) for 3-HANA, KYNA, and QUIN. Transfer for KYNA, 3-HANA, and ANA also appeared to be limited by plasma protein binding. The results demonstrate the saturable transfer of L-KYN across the blood-brain barrier and suggest that circulating L-KYN, 3-HKYN, and ANA may each contribute significantly to respective cerebral pools. In contrast, QUIN, KYNA, and 3-HANA cross the blood-brain barrier poorly, and therefore are not expected to contribute significantly to brain pools under normal conditions.
Fukui
S
S
Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892.
Schwarcz
R
R
Rapoport
S I
SI
Takada
Y
Y
Smith
Q R
QR
D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D007736:Kynurenic Acid / Q000493:pharmacokinetics; D007737:Kynurenine / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D017378:Quinolinic Acid; D011805:Quinolinic Acids / Q000493:pharmacokinetics; D051381:Rats; D011919:Rats, Inbred Strains; D062367:ortho-Aminobenzoates / Q000493:pharmacokinetics
D011805:Quinolinic Acids; D062367:ortho-Aminobenzoates; C031385:anthranilic acid; C005045:3-hydroxykynurenine; D007737:Kynurenine; D017378:Quinolinic Acid; D007736:Kynurenic Acid