Transformed rat tracheal epithelial cells (U2) were found to be 3.6-fold more sensitive than lung fibroblasts (RLF) to paraquat. Although the toxic effects of paraquat are associated with the generation of very active Superoxides, U2 cells contained higher levels of Superoxide dismutase and catalase than RLF cells. On the other hand, the specific activities of both NADPH-cytochrome c reductase and glucose-6-phosphate dehydrogenase (G6DP) were 3- to 4-fold higher in U2 cells than in RLF cells. Treatment with dehydroepiandrosterone (DHEA) and epiandrosterone (EPI), G6PD inhibitors, significantly decreased the intracellular NADPH and protected U2 cells from paraquat toxicity. Since DHEA and EPI treatment did not affect the uptake of paraquat, our results suggest that paraquat sensitivity may depend on the redox cycling-associated activities of paraquat.