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Deferoxamine toxicity in hepatoma and primary rat cortical brain cultures

Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, California 92350, USA; Pediatric Critical Care, St. Luke's Regional Medical Center, 190 East Bannock Street, Boise, Idaho 83712-9987, USA

R Kisling

Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, California 92350, USA

J Thompson

Department of Biology, California State University, San Bernardino, California 92407, USA

M A Kirby

Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, California 92350, USA

Deferoxamine is commonly used for treatment of iron intoxication. Because the usual dose is unable to chelate sufficient iron before severe injury occurs, "high-dose" deferoxamine treatment has been proposed. However, several authors have reported severe toxicity after deferoxamine therapy. Although the hemodynamic effects are well described, the cellular toxicity of deferoxamine is unknown. Accordingly, we investigated the cellular toxicity of deferoxamine using in vitro techniques in two cell lines. Brain cells were harvested from fetal rats and cultured for 14-21 days beforedeferoxamineexposure.Usingsimilartechniques,rat hepatoma cells were grown until confluent. Deferoxamine was added to the cultures to achieve final concentrations of 200-800 µg/ml, corresponding to in vivo infusion rates of 15-60mg/kg/h.Deferoxaminewasremovedafter3or6days by changing the medium. Subtoxic FeCl₃ (500 mg/dl) was concurrently added to identical cultures to determine if deferoxamine potentiated iron toxicity. Cell viability was measured by a colorimetric assay. The addition of deferoxamine (0.2, 0.4, 0.8 mg/ml) significantly decreased cell viability in both cell groups. The effect of deferoxamine on primary cortical brain cultures was similar for the three concentrations used, and was similar when examined either 72 h or 6 days later. In contrast, hepatoma cell cultures evidencedadose-dependentcelllossthatincreasedwiththe lengthofexposure.TheadditionofsubtoxicamountsofFeCl₃(500 µg/dl) in the presence of deferoxamine was protective in all cultures, and abolished deferoxamine-induced cell loss. Interestingly, the addition of serum albumin significantlyreducedtheamountofironpresentincells,suggesting its potential use to treat iron toxicity. These results suggest that deferoxamine, in the absence of iron, is toxic to cortical brain and hepatoma cells in vitro.

Key Words: Iron toxicity • deferoxamine • MTT • primary cortical cells • hepatoma cells • neurons • FeCl3

Human & Experimental Toxicology, Vol. 20, No. 7, 365-372 (2001)
DOI: 10.1191/096032701680350532


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