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R Kannan, JF Kuhlenkamp, M Ookhtens and N Kaplowitz
Department of Medicine, University of Southern California School of Medicine, Los Angeles.
We showed previously that glutathione (GSH) may cross the blood-brain barrier intact by a saturable low affinity transport process (Km approximately 6 mM) (Kannan et al., J. Clin. Invest. 85: 2009-2013, 1990). In the present report, breakdown and resynthesis of GSH as the mechanism of apparent GSH uptake were excluded further because > 87% of injected 35S-cysteine taken up at the blood-brain barrier remained unchanged with negligible incorporation into GSH. In an effort to characterize further this GSH transport system, we have studied the influence of a number of potential inhibitors on brain uptake index (BUI) of GSH in rats pretreated with a gamma-glutamyl transpeptidase inhibitor, acivicin. The BUIs of tracer 35S-GSH uptake in the presence or absence of 1 to 20 mM cysteine, glutathione disulfide, gamma- glutamylglutamate, gamma-glutamyl-p-nitroanilide and 2- aminobicyclo(2,2,1)heptane-2-carboxylic acid did not differ significantly from each other. However, S-alkyl glutathiones (hexyl and octyl), sulfobromophthalein-glutathione, glutathione monoethyl ester, probenecid (5 mM) and ophthalmic acid (10 mM) inhibited GSH uptake significantly. Inhibition of GSH uptake by sulfobromophthalein- glutathione and GSH-monoethyl ester was concentration-dependent with apparent Ki approximately 0.016 and 0.083 mM, respectively. There was a decline in GSH-BUI as a function of age in both acivicin and nonacivicin-pretreated rats during the growth and developmental period from 25 to 135 days of age (100-500 g b.wt.). The decrease in BUI with age was specific for GSH; cysteine uptake did not change and no difference in diffusible (H2O) and nondiffusible (sucrose) components was found in this age range.(ABSTRACT TRUNCATED AT 250 WORDS)
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