Investigations into the mechanism of paraquat toxicity utilizing a cell culture system
Carmines, E.L.; Carchman, R.A.; Borzelleca, J.F.
Toxicology and Applied Pharmacology 58(3): 353-362
ISSN/ISBN: 0041-008X PMID: 7245208 DOI: 10.1016/0041-008x(81)90087-9
Paraquat (PQ) and diquat (DQ) [herbicides] produced a dose-dependent inhibition of cellular proliferation in mouse macrophage-like P388D, cells in culture. DQ (IC50 [median inhibitory concentration] = 1.92 .times. 10-5 M) was not significantly more potent than PQ (IC50 = 1.05 .times. 10-4 M). The dose-response lines did not deviate significantly from parallelism. Both herbicides had no effect on lipid peroxidation. Ferric pyrophosphate, a known stimulator of lipid peroxidation, produced a dose- and time-dependent stimulation. Effects produced by ferric pyrophosphate indicated that the absence of an effect due to PQ or DQ was not due to an insensitivity of the system. Increasing O2 tension did not enhance toxicity (as measured by cell growth) of PQ. There was no indication of PQ-induced membrane damage as indicated by the leakage of the cytoplasmic enzyme, lactate dehydrogenase. The effect of PQ and DQ on macromolecular synthesis was evaluated as a possible mechanism by which cell growth was inhibited. Both herbicides produced a dose- and time-dependent inhibition of DNA synthesis. DQ, but not PQ, inhibited RNA synthesis. PQ or DQ did not alter protein synthesis. Inhibition of DNA synthesis was not due to an alteration of the availability of the precursors. Mitochondrial function, as measured by O2 consumption, was not affected, suggesting that the inhibition of DNA synthesis was not due to an alteration of energy metabolism. Cyclic nucleotide levels were also not affected, suggesting that the inhibition of cell growth and DNA synthesis was not due to an alteration of cellular control processes. Inhibition of macromolecular synthesis may be involved in the molecular mechanism of toxicity of PQ.