Specific induction of metallothionein synthesis by mitochondrial oxidativestress

Metallothionein (NIT), a sulfhydryl-rich protein, may be increased by admin istration of a variety of agents, including metals, cytokines and oxidative stress agents. Mitochondria are a major source of reactive oxygen species, but antioxidant systems against mitochondrial free radicals are not fully understood. In this study, we examined the induction of MT synthesis by adm inistration of mitochondrial-specific reactive oxygen generators such as an timycin A (AA), an electron transfer inhibitor, and 2,4-dinitrophenol (DNP) , an uncoupling agent. Subcutaneous administration of AA to mice significan tly increased the hepatic MT concentration in a dose- and time-dependent ma nner. AA slightly elevated glutathione peroxidase (GSHPx) activity, but the rate of increase in GSHPx (1.3-fold) was smaller than that in MT (11.8-fol d). Other antioxidants such as catalase, manganese-superoxide dismutase (Mn -SOD), copper/zinc-superoxide dismutase (Cu/Zn-SOD) and GSHPx were not acti vated by AA treatment. Moreover, administration of DNP induced the synthesi s of MT in the liver. Although DNP slightly elevated Mn-SOD activity, the r ate of increase in Mn-SOD (1.3-fold) was smaller than that in MT (3.7-fold) . Other antioxidants such as catalase, Cu/Zn-SOD and GSHPx were not activat ed by DNP treatment. These data suggest that MT plays a major role in prote ction against oxidative stress induced in mitochondria. (C) 2001 Elsevier S cience Inc. All rights reserved.