TRANSFECTION WITH HUMAN COPPER-ZINC SUPEROXIDE-DISMUTASE INDUCES BIDIRECTIONAL ALTERATIONS IN OTHER ANTIOXIDANT ENZYMES, PROTEINS, GROWTH-FACTOR RESPONSE, AND PARAQUAT RESISTANCE

Transfection of a pSV2 human copper-zinc superoxide dismutase expressi on vector into murine fibroblasts resulted in stable transgenic clones producing increased amounts of copper-zinc superoxide dismutase. Two classes of transfectants were observed and were characterized by the p resence or absence of an increase in endogenous glutathione peroxidase activity. In addition, increases and decreases in individual clones i n the activities of manganese superoxide dismutase, glutathione reduct ase, and NADPH-reductase were detected. In general, these alterations in enzyme activity correlated to the cellular glutathione peroxidase/c opper-zinc superoxide dismutase ratio. Parameters of cellular physiolo gical functions were also altered, including cell division time, FGF a nd EGF response, fibronectin content, paraquat resistance, hydrogen pe roxide release into media, and sensitivity to radiation. Some of these cellular parameters were also bidirectional and reflected the cellula r glutathione peroxidase/copper-zinc superoxide dismutase ratio. Our r esults indicate that small deviations from the normal physiological co pper-zinc superoxide dismutase/seleno-glutathione peroxidase ratios ca n have pronounced effects on other antioxidant enzymes, growth rate, g rowth factor response, and expression of proteins normally not associa ted with oxygen metabolism.