Hazards of antioxidant combinations containing superoxide dismutase

Mark S. Paller, John W. Eaton

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


Oxygen free radical scavengers protect against ischemia/reperfusion injury of the kidney in vivo and against hypoxia/ reoxygenation (H/R) injury of renal cells in several in vitro systems. In an attempt to maximize renal protection we tested several antioxidants in combination; the individual components had previously reduced reoxygenation injury of hypoxic renal epithelial cells. Both glutathione (GSH; 1 mM) and Cu,Zn-SOD provided significant protection against posthypoxic injury. Surprisingly, the combination of Cu,Zn-SOD plus GSH eliminated protection entirely and was highly toxic to normoxic cells. The toxicity of Cu,Zn-SOD + GSH was not prevented by the iron chelator deferoxamine and was only slightly reduced by the hydroxyl scavenger DMTU. Catalase reversed the toxicity of Cu,Zn-SOD + GSH and provided net protection. Direct measurement of intracellular peroxides using 2,7-dichlorofluorescin quantitated by laser cytometry also revealed enhanced generation of peroxides by cells during H/R when Cu,Zn-SOD + GSH was present. GSSG was less toxic than GSH when combined with Cu,Zn-SOD. Importantly, the combination of Mn-SOD + GSH provided superior protection to either agent alone. In the presence of added GSH, heated or autoclaved Cu,Zn-SOD was still toxic, whereas SOD free of chelatable Cu++ was benign. In the presence of GSH, Cu++ derived from SOD may promote the formation of toxic thionyl radicals, metal-centered radicals, and/or H2O2, thereby causing cell injury. Great care should be used in designing and interpreting studies employing combinations of antioxidants.

Original languageEnglish (US)
Pages (from-to)883-890
Number of pages8
JournalFree Radical Biology and Medicine
Issue number5
StatePublished - May 1995
Externally publishedYes

Bibliographical note

Funding Information:
Acknowledgements -- Supported by an American Heart Association Grant-in-Aid (MSP), an extramural grant from Baxter Healthcare Corporation (MSP), and NIH grant HL 50136 (JWE).


  • Amyotrophic lateral sclerosis
  • Copper
  • Free radicals
  • Glutathione
  • Hypoxia
  • Kidney
  • Reoxygenation
  • Superoxide dismutase


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