Cytopathogenic effects of atoxyl, an ototoxic compound, on human diploid fibroblasts in vitro.
Atoxyl, an arsenic compound, may cause degeneration in vivo of the inner ear including cells of the stria vascularis and hair cells. The mechanism behind the cytotoxic effect is not known. The effects of atoxyl at the subcellular level were investigated in this study using human diploid embryonic lung fibroblasts in monolayer cultures as an in vitro model system. Atoxyl caused a subtle but significant increase in the permeability of the fibroblast plasma membrane, as measured by release of a low molecular weight cytoplasmic marker (alpha-amino isobutyric acid). At higher concentrations or after longer incubation times, protein synthesis was impaired. This effect occurred in parallel with alterations in the cellular morphology as viewed by light microscopy. In the final stages of atoxyl intoxication the cells released also a higher molecular weight marker (nucleotide), indicating a further increased membrane permeability following the primary damage. It is concluded that atoxyl exerts a dual effect on the human fibroblasts, namely on membrane permeability and protein synthesis. Although the concentrations used were higher than those exerting the ototoxic effects in vivo, the prolonged exposure times to low concentrations obtained in whole animals may very well compensate for this fact. The effects observed in the in vitro fibroblast model system may thus be relevant to the mechanism of action of atoxyl during induction of ototoxic effects in vivo.
D000814:Aniline Compounds / Q000494:pharmacology; D001152:Arsenicals / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D004171:Diploidy; D005347:Fibroblasts / Q000187:drug effects / Q000648:ultrastructure; D006311:Hearing Disorders / Q000139:chemically induced*; D006801:Humans; D066298:In Vitro Techniques; D009994:Osmolar Concentration; D014176:Protein Biosynthesis; D013997:Time Factors
D000814:Aniline Compounds; D001152:Arsenicals