Methylmercury inhibits cysteine uptake in cultured primary astrocytes, butnot in neurons

The maintenance of adequate intracellular glutathione (GSH) concentrations is dependent on the availability and transport of the rate-limiting substra te, cysteine. A suggested mechanism of methylmercury (MeHg) neurotoxicity i n brain involves the formation of oxygen radicals, and a decrease in intrac ellular levels of GSH Recently, we have characterized various cysteine tran sport systems (both Na+-dependent and -independent) in cerebrocortical astr ocytes and hippocampal neurons. The present study was carried out to invest igate the effect of MeHg on cysteine uptake in both astrocytes and neurons, and to determine whether cysteine transport is differentially affected in the two cell types by MeHg treatment. Sixty-minute pretreatment with MeHg c aused significant concentration-dependent inhibition in cysteine uptake in astrocytes, but not in neurons. As most of the cysteine transport is Na+-de pendent (80-90% of total), additional studies focused on MeHg's effect on t he Na+-dependent cysteine transporters X-AG and ASC. An additive inhibitory effect on cysteine uptake was observed in astrocytes treated with MeHg (5 muM) plus sub-maximal inhibitory concentrations (0.1 and 0.5 mM) of threo-b eta -hydroxy-aspartate (THA), a specific inhibitor of the Na+-dependent tra nsporter, X-AG-, compared to astrocytes treated with MeHg (P <0.001) or THA alone (P <0.05). There was no additive effect of MeHg and maximal inhibito ry concentrations of THA (1.0 and 5.0 mM) on astrocytic cysteine uptake inh ibition. Additional studies examined the sensitivity of the Na+-dependent A SC transport system to MeHg treatment. Maximal inhibitory concentration Of L-serine (10 mM) alone had a rather modest inhibitory effect on cysteine up take, and when applied in the presence of MeHg there was no additive effect . These results suggest that the inhibition of cysteine uptake by MeHg in a strocytes occurs through specific inhibition of both the X-AG- as well as t he ASC transport system. (C) 2001 Elsevier Science BY. All rights reserved.