Transport and metabolism of glutathione isopropyl ester in cerebrospinal fluid.
The transport of glutathione (GSH) or glutathione isopropyl ester (GSH isopropyl ester) to the cerebrospinal fluid (CSF) in rats was estimated by levels of GSH or GSH isopropyl ester and their metabolites in CSF 30 min after the intravenous administration of GSH or GSH isopropyl ester (300 mg/kg). Although the CSF uptake of GSH isopropyl ester was almost equal to that of GSH as evidenced by about a two-fold increase in the amount of non-protein sulfhydryl groups in CSF, the sum of GSH isopropyl ester and GSH concentrations in the CSF after GSH isopropyl ester treatment was increased by 32% compared with saline-treated controls. On the other hand, treatment with GSH had no significant increase in GSH levels in CSF but increased its metabolite levels, such as cysteinyl-glycine and cysteine. GSH isopropyl ester was less metabolized than GSH. GSH isopropyl ester had low affinity to purified gamma-glutamyl transpeptidase, a key enzyme for metabolism of GSH in the choroid plexus, supporting the finding that GSH isopropyl ester is more stable than GSH in CSF. These results are compatible with our previous report (Yamamoto et al. (1993) showing that the protective action of GSH isopropyl ester against cerebral ischemia was greater than that of GSH in rats. GSH isopropyl ester may be a useful agent which protects the brain from the damage associated with oxygen-related toxicities by increasing GSH levels in the CSF.
Shikama
H
H
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Ohta
A
A
Iwai
A
A
Koutoku
H
H
Umeda
M
M
Noguchi
K
K
Takeda
M
M
Ohhata
I
I
D000818:Animals; D001692:Biological Transport; D002545:Brain Ischemia / Q000188:drug therapy; D003545:Cysteine / Q000134:cerebrospinal fluid; D004151:Dipeptides / Q000134:cerebrospinal fluid; D016166:Free Radical Scavengers; D005978:Glutathione / Q000031:analogs & derivatives* / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013438:Sulfhydryl Compounds / Q000134:cerebrospinal fluid; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D004151:Dipeptides; D016166:Free Radical Scavengers; D013438:Sulfhydryl Compounds; C097917:cysteinylglycine isopropyl ester; C028505:cysteinylglycine; C058293:glutathione monoisopropyl ester; D005723:gamma-Glutamyltransferase; D005978:Glutathione; D003545:Cysteine