Enhanced cadmium cytotoxicity in A549 cells with reduced glutathione levels is due to neither enhanced cadmium accumulation nor reduced metallothionein synthesis.
Glutathione (GSH) depletion sensitizes human lung carcinoma (A549-T27) cells to the cytotoxic effects of Cd++. The effects of GSH depletion on Cd++ accumulation and Cd++-induced metallothionein (MT) content were investigated to determine the possible role of these Cd++ responses in the sensitization process. Cellular GSH was depleted to 20% to 25% of control levels with buthionine sulfoximine (BSO), or diethyl maleate (DEM), respectively. Neither treatment significantly affected Cd++-induced accumulation of exogenous 35s-cysteine into intracellular MT in a dose-dependent fashion. The results indicate that neither enhanced Cd++ accumulation nor reduced MT synthesis plays a primary role in affecting enhanced Cd++ cytotoxicity in A549 cells with reduced GSH levels. Although BSO inhibition of GSH synthesis enhanced MT synthesis, it sensitized the cells to Cd++, which suggests an additive effect of GSH and MT in cadmium cytoprotection. This observation also raises the possibility that intracellular cysteine levels limit Cd++-induced MT accumulation rates.
Kang
Y J
YJ
Department of Zoology, Iowa State University, Ames.
Clapper
J A
JA
Enger
M D
MD
D019328:Buthionine Sulfoximine; D002104:Cadmium / Q000378:metabolism / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D008298:Maleates / Q000494:pharmacology; D008668:Metallothionein / Q000096:biosynthesis*; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D013462:Sulfur Radioisotopes; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000378:metabolism
D008298:Maleates; D013462:Sulfur Radioisotopes; D002104:Cadmium; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D008668:Metallothionein; C014476:diethyl maleate; D005978:Glutathione