Induction of cystine transport activity in isolated rat hepatocytes by sulfobromophthalein and other electrophilic agents.

The uptake of cystine in isolated rat hepatocytes was enhanced after incubation of the cells with sulfobromophthalein. The enhancement was time- and dose-dependent, with a lag of about 6 hr, and an approximately 4-fold increase in the activity occurred after 24 hr with 0.2 mM sulfobromophthalein. Actinomycin D or cycloheximide completely blocked the time-related increase in the uptake. The enhanced activity of cystine uptake was almost entirely Na+-independent and inhibited by some anionic amino acids, such as glutamate. The uptake of glutamate was also enhanced by sulfobromophthalein. It is concluded that sulfobromophthalein induces the activity of the Na+-independent, anionic amino acid transport system (System x-c) which mediates the transport of cystine. Some other electrophilic agents also enhanced the cystine uptake. The glutathione level of hepatocytes was rapidly reduced by sulfobromophthalein to about 10% of the control level at 6 hr, but at 12 hr it began to rise. It seems likely that this restoration resulted from the induced activity of the cystine uptake because inhibitors of the cystine uptake blocked the restoration and because the uptake of other sulfur amino acids was not enhanced significantly by sulfobromophthalein. System x-c may thus participate in the detoxication of electrophilic agents in hepatocytes.