tri-n-Butyltin: a membrane toxicant.
Increased use of the biocidal compound tri-n-butyltin (TBT) in antifouling paints has prompted research aimed at determining the mechanism for TBT toxicity. Past investigations indicate that the primary cellular target for TBT is the cell membrane. Erythrocyte suspensions treated with TBT concentrations 2 greater than or equal to 5 microM undergo hemolysis described by a sigmoidal kinetic pattern. Transformation of cell shape from discocyte to echinocyte occurs at TBT concentrations greater than or equal to 0.1 microM, indicating that the compound enters the outer membrane bilayer. TBT at concentrations greater than or equal to 10 microM forms electron-dense aggregates that are intercalated within plasma membranes as viewed in ultrathin sections by transmission electron microscopy. Qualitative X-ray microanalysis of these aggregates confirms the presence of tin. The size of these structures can be modified by either 10 mM cyanide or 2,3-dimercaptopropanol (British Anti-Lewisite, BAL). Adding 10 mM cyanide to hemolytic TBT concentrations resulted in a synergistic stimulation of hemolysis attributable to high cyanide anion concentrations in or near the cell membrane. The elevated cyanide anion levels are thought to contribute to membrane lysis. The lipophilic dimercapto compounds BAL, dithiothreitol, and 2,3-dimercaptosuccinate are effective inhibitors of TBT-induced lysis. Water-soluble 2,3-dimercapto-1-propane sulfonate, a BAL analog, was largely ineffective as an inhibitor. The detailed molecular mechanism for TBT-induced membrane lysis is not yet clear. Cellular ATP depletion could be induced by TBT as well as by delipidation of anionic phospholipids or even formation of tributylstannylperoxy radicals, resulting in lipid peroxidation.
Gray
B H
BH
Naval Dental School, NMCNCR, Bethesda, Maryland 20814-5007.
Porvaznik
M
M
Flemming
C
C
Lee
L H
LH
D055598:Chemical Phenomena; D002621:Chemistry; D004112:Dimercaprol / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004910:Erythrocyte Membrane / Q000187:drug effects* / Q000648:ultrastructure; D004913:Erythrocytes, Abnormal / Q000187:drug effects / Q000648:ultrastructure; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008854:Microscopy, Electron; D013052:Spectrometry, X-Ray Emission; D004113:Succimer / Q000494:pharmacology; D014220:Trialkyltin Compounds / Q000009:adverse effects*; D014494:Unithiol / Q000494:pharmacology
D014220:Trialkyltin Compounds; D004112:Dimercaprol; D014494:Unithiol; C011559:tributyltin; D004113:Succimer; D004229:Dithiothreitol