the transport of amino acids by both normal rat hepatocytes and rat H4 hepatoma cells has been tested for inactivation by sulfhydryl-preferring, protein-modifying reagents. Amino acid transport by systems A, ASC, N, L, and y+ in the H4 hepatoma cells was relatively resistant to inactivation by the alkylating reagent N-ethylmaleimide (NEM), whereas uptake mediated by systems A, ASC, and L was decreased in normal rat hepatocytes. In contrast, nearly all of the amino acid transport systems in both cell types were inhibited strongly by p-chloromercuribenzene sulfonate (PCMBS). The exceptions were the H4 hepatoma system y+ activity (72% of control) and system L-mediated uptake (121% of control) in normal hepatocytes. Although transport via system A was equally sensitive to inhibition by PCMBS in both cell types, substrate-dependent protection from this inactivation was observed only in the H4 hepatoma cells. These results illustrate the significant differences that exist between normal and transformed liver cells in respect to amino acid transport inactivation by sulfhydryl reagents.