Cadmium (Cd) inhibited the activities of Na(+)-K+ ATPase (IC50 = 5.0 x 10(-5) M), K(+)-p-nitrophenyl phosphatase (PNPPase) (IC50 = 4.0 x 10(-5) M) and 3H-ouabain binding (IC50 = 7.5 x 10(-5) M) in rat brain microsomes. Monothiols (cysteine but not glutathione and D-penicillamine) and dithiols (dimercaprol, dimercaptosuccinic acid and dithiothreitol) offered varied levels of protection against Cd-inhibition of Na(+)-K+ ATPase. Protection of Na(+)-K+ ATPase by these sulfhydryl (SH) agents was higher at 7.5 as compared to 8.5 pH. The present data suggest that Cd-inhibited Na(+)-K+ ATPase, by interfering with phosphorylation of enzyme molecule and dephosphorylation of the enzyme-phosphoryl complex and exerts a similar effect to that of SH-blocking agents.