Metallothionein-enriched hepatocytes are resistant to ferric nitriloacetate toxicity during conditions of glutathione depletion

Metallothionein (MT) is involved not only in heavy metal homeostasis/detoxification but also in radical scavenging, yet the relevance to other antioxidant systems and physiological significance under oxidative stress has not been clarified. We studied that ability of MT, induced by zinc and cadmium, to protect against oxidative damage induced by ferric nitrilotriacetate (Fe-NTA) in glutathione depleted primary cell cultures. Treatment with Fe-NTA resulted in significant decreases in cell survival and increases in medium LDH activity in control cells following depletion of glutathione. The toxic effects of Fe-NTA were modulated in Zn-MT-enriched cells. In glutathione-depleted cells, but not in non-treated cells, Cd-binding properties of cellular Zn-MT decreased with increasing concentration of Fe-NTA. Both Zn-MT and Cd-MT-enriched cells were resistant to higher doses of Fe-NTA. These results indicate that MT may act a cellular radical scavenger in the absence of GSH. Thus, MT may function as a secondary antioxidant in a cellular protection system.