Protection against cisplatin toxicity by administration of glutathione ester.

Abstract

The role of cellular glutathione in the prevention of toxicity due to the anti-cancer drug cisplatin (cis-diamminedichloroplatinum) was explored in mice treated with buthionine sulfoximine (BSO), a selective inhibitor of gamma-glutamylcysteine synthetase (and therefore of glutathione synthesis), and with glutathione and glutathione monoisopropyl ester. Pretreatment of mice with BSO enhanced the lethal toxicity of cisplatin by about twofold. Administration of glutathione ester (dose, 2.5-7.5 mmol/kg) protected against lethal cisplatin toxicity; glutathione was also effective, but much less so. Glutathione ester, in contrast to glutathione, is effectively transported into cells and split to glutathione intracellularly. The previous findings that administered glutathione does not protect against lethal toxicity due to cadmium ions and mercuric ions, whereas glutathione ester does, suggest that intracellular glutathione is required for protection against these heavy metal ions. That administration of glutathione has a protective effect on cisplatin toxicity suggests that the toxic effects of cisplatin may be exerted both intracellularly and extracellularly, and that extracellular glutathione (or its degradation products) may form a complex with cisplatin extracellularly. The finding that glutathione ester is more effective than glutathione in protecting against the toxicity of cisplatin suggests that use of glutathione ester may be therapeutically advantageous.

• Authors: M E Anderson, A Naganuma, A Meister
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 4 Issue 14 Pg. 3251-5 (Nov 1990) ISSN: 0892-6638 [Print] United States
• PMID: 2227215 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Methionine Sulfoximine
• Buthionine Sulfoximine
• glutathione monoisopropyl ester
• Creatinine
• Glutathione
• Cisplatin

Topics

• Animals
• Blood Urea Nitrogen
• Buthionine Sulfoximine
• Cisplatin (toxicity)
• Creatinine (blood)
• Glutathione (analogs & derivatives, blood, metabolism, pharmacology, therapeutic use)
• Kidney (metabolism)
• Kidney Diseases (blood, chemically induced, prevention & control)
• Liver (metabolism)
• Male
• Methionine Sulfoximine (analogs & derivatives, pharmacology)
• Mice