Decreased zinc toxicity resulting from doxorubicin without increased GSSG export in three human lung cell lines.
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.
Walther
U I
UI
Walther-Straub-Institut für Pharmakologie und Toxikologie der Ludwig-Maximilians-Universität München, Nussbaumstr. 26, 80336 München, Germany.
Walther
S C
SC
Mückter
H
H
Fichtl
B
B
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000502:physiology; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism*; D005980:Glutathione Reductase; D006801:Humans; D008168:Lung / Q000166:cytology / Q000187:drug effects*; D008715:Methionine / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000502:physiology; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D013880:Thioredoxin-Disulfide Reductase; D015032:Zinc / Q000633:toxicity*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004317:Doxorubicin; D005978:Glutathione; D019803:Glutathione Disulfide; D005980:Glutathione Reductase; D008715:Methionine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009247:NADH, NADPH Oxidoreductases; D013880:Thioredoxin-Disulfide Reductase; D015032:Zinc; C424443:Txnrd3 protein, mouse