CYTOTOXICITY OF HEAVY-METALS IN THE HUMAN SMALL-INTESTINAL EPITHELIAL-CELL LINE I-407 - THE ROLE OF GLUTATHIONE

Cytotoxicities of metal salts were determined in the intestinal epithelial cell line I-407 in microwell culture plates over 48 h using the widely utilized and accepted neutral red uptake procedure. Rank order cytotoxicities induced by the metal salts (in terms of LC50 values) were found to be HgCl2 (32 mu M) > CdCl2 (53 mu M) > CuCl2 (156 mu M) > Tl2SO4 (377 mu M) > Pb(NO3)(2) (1.99 mM). Combined administration of the two most toxic metals at their LC50's showed that their toxicities were not additive or synergistic. The role of glutathione in determining toxicity induced by the metal salts in these cells was assessed by inhibition of its synthesis. Buthionine sulfoximine pretreatment at 1 mM, which was not toxic to the cells, caused sustained reduction in cellular glutathione content(to 13.8% after 48 h) and increased toxicities induced by HgCl2 (5.7-fold) and CuCl2 (1.44-fold) as shown by reductions in the LC50 values. Toxicity induced by the other metals remained unaffected. Administration of glutathione with either HgCl2 or CdCl2 did not protect the cells against their toxicity, and in the case of cadmium its toxicity was exacerbated N-Acetylcysteine diminished toxicity induced by mercury but not cadmium.