Effect of oral glutathione monoethyl ester and glutathione on circulating and hepatic sulfhydrils in the rat.
Glutathione (GSH) plays an important role in the detoxification of reactive metabolites of oxygen and xenobiotics and as a source of cysteine. Since several clinical situations characterized by low circulating and intracellular GSH have been identified, there is a growing interest in pharmacological interventions to correct a deranged sulfhydril status. Therefore, the systemic bioavailability of orally administered GSH and glutathione monoethyl ester (GSHE) was examined in the rat. Following the intraduodenal administration of 0.5 mmol/kg of GSH and GSHE there was no significant increase in the concentrations of cysteine and GSH in plasma, but hepatic cysteine and GSH increased significantly, albeit transiently. Five mmol/kg of GSH and GSHE significantly increased circulating and hepatic cysteine and GSH. Following the administration of 0.5 and 5 mmol/kg of GSHE low concentrations of the ester were found in plasma and the liver, indicating that GSHE is not readily absorbed from the gastrointestinal tract, although it is not a substrate for gamma-glutamyl-transferase. GSHE resulted in a delayed release of cysteine and GSH compared to GSH, such that the concentrations of GSH and cysteine in liver and plasma were significantly higher 2 h after administration of GSHE than after GSH. The data indicate that the bioavailability of GSH and GSHE is low in the rat. Orally administered GSH and GSHE do not affect the circulating concentrations of GSH and cysteine unless very high doses are administered, but increase hepatic cysteine and GSH at lower doses because of the efficient extraction by the liver of cysteine originating from the breakdown of GSH and GSHE in the gut.
Grattagliano
I
I
Department of Clinical Pharmacology, University of Bern, Schweiz.
Wieland
P
P
Schranz
C
C
Lauterburg
B H
BH
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D003545:Cysteine / Q000097:blood; D004195:Disease Models, Animal; D004386:Duodenum / Q000187:drug effects / Q000378:metabolism; D005978:Glutathione / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D007408:Intestinal Absorption / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D011837:Radiation-Protective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D011837:Radiation-Protective Agents; D013438:Sulfhydryl Compounds; C042431:S-ethyl glutathione; D005723:gamma-Glutamyltransferase; D005978:Glutathione; D003545:Cysteine