Importance of hydrogen peroxide in nitrofurantoin-induced cytotoxicity: evidence from an inbred catalase-deficient strain of mice.

Significant pulmonary toxicity is associated with the use of nitrofurantoin; however, the mechanism of cellular toxicity remains poorly characterized. By using a novel in vitro red blood cell (RBC) chromium 51 cytotoxicity assay, cell injury induced by nitrofurantoin was quantified with normocatalasemic BALB/c RBCs and hypocatalasemic (but otherwise genetically identical) CCN RBCs as target cell populations. Nitrofurantoin at concentrations of 2 x 10(-4) and 4 x 10(-4) mol/L resulted in significant injury to normocatalasemic RBCs with a cytotoxic index (CI) of 21.7% +/- 3.7% and 65.3% +/- 3.7% (p less than 0.05, both comparisons). This injury was substantially increased when nitrofurantoin (2 x 10(-4) and 4 x 10(-4) mol/L was incubated with hypocatalasemic RBCs, resulting in CIs of 59.0% +/- 7.4% and 91.0% +/- 2.0% respectively (p less than 0.05, both comparisons with normocatalasemic RBCs). Direct oxidant-mediated cytotoxicity induced by either H2O2 or the superoxide anion radical (as generated by xanthine-xanthine oxidase) also resulted in more significant injury to hypocatalasemic RBCs than to normocatalasemic RBCs (p less than 0.05, both comparisons). Catalase levels of CCN RBCs were approximately 7% of control BALB/c RBC values; however, the activities of superoxide dismutase and glutathione peroxidase were identical in both populations of RBCs. This model, using genetically defined target cell populations, clearly demonstrates the importance of endogenous catalase in protecting against nitrofurantoin-induced cytotoxicity, suggesting that H2O2 is a critical intermediary in the direct cell injury mediated by the drug.

The effect of prostaglandin E1 or E2 on the in vitro blastogenic response of lymphocytes from normal and tumor-bearing mice.

The in vitro effect of exogenously added prostaglandin (PG) E1 or E2 over concentrations ranges of from 1 X 10(-4) to 1 X 10(-9) M were studied in order to determine their effect on the in vitro lymphocyte proliferation of thymic and splenic T and B cells from normal and tumor-bearing CD2F1 mice. It was found that PGE1 generally caused greater inhibition of blastogenesis than did PGE2 when reacted with splenic lymphocytes from normal mice. Indeed, PGE2 was found to be stimulatory for both Con A- and LPS-sensitive normal splenic lymphocytes. Both PGE1 and PGE2 caused potent inhibition of Con A- and PHA-sensitive splenic lymphocytes from the tumor-bearing mice. Additionally, PGE2 was found to stimulate the LPS-reactive lymphocytes from the tumored mice. PGE1 and PGE2 both inhibited the Con A- and PHA-reactive thymic lymphocytes from normal mice at the lower concentrations studied, i.e., 10(-4) to 10(-6) M. Thereafter, at concentration ranges of from 10(-7) to 10(-9) M both PGE1 and PGE2 were both found to be stimulatory. Finally, both PGE1 and PGE2 at all concentrations studied, strongly inhibited the thymic lymphocytes from tumored mice.