Decreased zinc toxicity resulting from doxorubicin without increased GSSG export in three human lung cell lines

• Published in: Biological trace element research 2004, Vol.102 (1-3), p.91-104
• Main Authors: Walther, U. I, Walther, S. C, Mückter, H, Fichtl, B
• Format: Article
• Language: English
• Subjects: ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Cadmium; Cell Line; Cell Line, Tumor; Cells; Cytotoxicity; Doxorubicin; Doxorubicin - pharmacology; Drug resistance; Drug Resistance, Multiple - physiology; Excretion; Glutathione; Glutathione - metabolism; Glutathione Disulfide - metabolism; Glutathione Reductase; GSH; Heavy metals; Humans; Lung; Lung - cytology; Lung - drug effects; Lungs; Methionine; Methionine - metabolism; Multidrug Resistance-Associated Proteins - physiology; NADH, NADPH Oxidoreductases - metabolism; proteins; Toxicity; Zinc; Zinc - toxicity
• ISSN: 0163-4984; 1559-0720; 0163-4984
• DOI: 10.1385/BTER:102:1-3:091

Zinc-mediated cytotoxicity is recognized, at least in part, by a decrease of reduced glutathione (GSH) and an increase in the oxidized form of glutathione (GSSG). Doxorubicin is a common inducer of multidrug-resistance-associated proteins and such proteins might, furthermore, be associated by an increased GSSG export rate. Therefore, zinc-mediated toxicity should be abolished after doxorubicin pretreatment. In the present study, zinc toxicity was characterized by methionine incorporation, glutathione content, and the GSSG/GSH ratio. Experiments were performed in three established lung cell lines comparing doxorubicin-pretreated cells with controls. Zinc-mediated toxicity was significantly decreased after pretreatment with doxorubicin as assessed by methionine-incorporation inhibition, GSH depletion, and/or GSSG increase in the two nonmalignant cell lines. Unexpectedly, zinc-associated GSSG export was not increased after doxorubicin pretreatment. This inconsistency might be explained as a result of a decreased zinc content in these cells, probably because of an increased export rate of zinc. The findings are in contradiction to the opinion of metal excretion by multidrug-resistance-associated proteins, matched to GSH conjugate excretion, as it is discussed for cadmium, for example.