In VitroMechanistic Toxicology Evaluation of the Antibiotic, Paldimycin Sodium, in Chang Liver Cells

Abstract

The basal in vitro cytotoxic potential of the antibiotic, paldimycin sodium, was investigated in Chang liver cells. The potential roles of lipid peroxidation, protein binding, and proteolytic enzyme activation in the cytotoxic mechanism of paldimycin were also examined. Cytotoxicity was assessed by measuring decreases in cell proliferation, increases in medium LDH activity due to cytoplasmic leakage, and morphological changes. Lipid peroxidation, protein binding, and proteolytic enzyme activation were investigated by co-treating cells with paldimycin and compounds which act as modifiers of the above pathways, such as antioxidants, sulphydryl compounds, and protease inhibitors, respectively.Paldimycin demonstrated a greater degree of basal cytotoxicity than was previously shown for several aminoglycoside and tetracycline antibiotics in Chang liver cells. Lipid peroxidation and proteolytic enzyme activation had no significant involvement in the observed cytotoxicity, whereas protein binding (more specifically, sulphydryl binding) was a principal mechanism of paldimycin-induced cytotoxicity in Chang liver cells. In addition, this sulphydryl binding was shown to be mediated via an exposed isothiocyanate moiety on the paldimycin molecule. The results of the co-treatment experiments described above are in agreement with data obtained in several other in vitro systems, including cell-free systems, isolated proteins, tissue homogenates, and primary isolates of cardiac myocytes.