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-glutamylcysteine synthetase in cultured rat
hepatocytes
Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853
Rat
hepatocytes cultured for 3 days in basal medium expressed low levels of
cysteine dioxygenase (CDO) and high levels of 
-glutamylcysteine
synthetase (GCS). When the medium was supplemented with 2 mmol/l
methionine or cysteine, CDO activity and CDO protein increased by
>10-fold and CDO mRNA increased by 1.5- or 3.2-fold. In contrast, GCS
activity decreased to 51 or 29% of basal, GCS heavy subunit (GCS-HS)
protein decreased to 89 or 58% of basal, and GCS mRNA decreased to 79 or 37% of basal for methionine or cysteine supplementation,
respectively. Supplementation with cysteine consistently yielded
responses of greater magnitude than did supplementation with an
equimolar amount of methionine. Addition of propargylglycine to inhibit
cystathionine -lyase activity and, hence, cysteine formation from
methionine prevented the effects of methionine, but not those of
cysteine, on CDO and GCS expression. Addition of buthionine sulfoximine
to inhibit GCS, and thus block glutathione synthesis from cysteine, did
not alter the ability of methionine or cysteine to increase CDO. GSH
concentration was not correlated with changes in either CDO or GCS-HS
expression. The effectiveness of cysteine was equivalent to or greater
than that of its precursors (S-adenosylmethionine,
cystathionine, homocysteine) or metabolites (taurine, sulfate). Taken
together, these results suggest that cysteine itself is an important
cellular signal for upregulation of CDO and downregulation of GCS.
glutathione; hepatocytes
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