Reversal of oxophenylarsine-induced inhibition of glucose uptake in MDCK cells.
It has been shown that oxophenylarsine (PhAsO) inhibits glucose uptake in MDCK cells. In addition to the known impairment of cellular energy metabolism, this inhibition may contribute to the acute toxicity of trivalent organic arsenicals. We have investigated the effect of BAL, DMPS, DMSA, and other sulfur compounds on cellular incorporation of [U-14C]PhAsO and their efficacy to revert PhAsO-induced inhibition of glucose uptake. In the presence of [U-14C]PhAsO (2 microM), the radiolabel was steadily accumulated by the cells over 150 min without any signs of severe cell damage (e.g., altered morphology, increased LDH release). A notable decrease of cellular ATP was only observed at 150 min, whereas within 30 min uptake of D-[6-(14)C]glucose was reduced to 40% of controls. When BAL, DMPS, or DMSA was added after 30 min, the inhibition of glucose uptake was reversed, accompanied by a decrease in cell-associated radiolabel from [U-14C]-PhAsO. Water-soluble DMPS and DMSA required longer times than BAL for comparable effects. 2,3-Bis(acetylthio)propanesulfonamide, a thioester derivative, and dithiothreitol, a 1,4-dithiol, were effective only with the highest concentration tested (200 microM). 2-Mercaptoethanol neither reversed inhibition of glucose uptake nor influenced [U-14C]PhAsO incorporation. Our results show that inhibition of glucose uptake is a very early event in PhAsO cytotoxicity which occurs before any decrease of cellular energy metabolism and/or full cellular loading with arsenic comes into effect. The more rapid onset of action of lipophilic BAL compared to PhAsO action.
Liebl
B
B
Walther-Straub-Institut für Pharmakologie und Toxikologie, Universität München, Federal Republic of Germany.
Mückter
H
H
Doklea
E
E
Fichtl
B
B
Forth
W
W
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000931:Antidotes / Q000494:pharmacology; D020261:Arsenic Poisoning; D001152:Arsenicals; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D004112:Dimercaprol / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology; D004285:Dogs; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005947:Glucose / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008623:Mercaptoethanol / Q000494:pharmacology; D004113:Succimer / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014494:Unithiol / Q000494:pharmacology
D000931:Antidotes; D001152:Arsenicals; D004791:Enzyme Inhibitors; D013449:Sulfonamides; D004112:Dimercaprol; C029341:oxophenylarsine; C093085:2,3-bis(acetylthio)propanesulfonamide; D014494:Unithiol; D008623:Mercaptoethanol; D000255:Adenosine Triphosphate; D004113:Succimer; D007770:L-Lactate Dehydrogenase; D005947:Glucose; D004229:Dithiothreitol