Accelerated hepatic arginine transport in the tumor-bearing rat

Arginine plays a pivotal role in regulating ureagenesis, polyamine biosynthesis, and nitric oxide production, metabolic pathways that may be stimulated in the liver of the tumor-bearing host. Normally, plasma arginine is excluded from the hepatocyte intracellular space by the low basal activity of its membrane transporter. We hypothesized that progressive malignant disease is associated with an increase in carrier-mediated arginine transport across the hepatocyte plasma membrane.

Twenty-four adult Fischer 344 rats were implanted subcutaneously with fibrosarcomas (TBR) and were studied when the tumors were small [10 +/- 1% of body weight (BW)], medium-sized (15 +/- 1% of BW), and large (25 +/- 1% of BW). Groups of control rats (n = 24) were pair-fed to match carcass weights of the three TBR groups. Livers were excised, and hepatocyte plasma membrane vesicles (HPMVs) were prepared by Percoll density gradient centrifugation. Arginine transport by HPMVs was assayed by a rapid mixing/filtration technique. Vesicle purity and functionality were assessed by membrane enzyme marker enrichments and transportability into an osmotically active space.

Arginine uptake by HPMVs was mediated by both saturable carrier-mediated (System y+) and nonsaturable (diffusion) components. The time course of arginine uptake in HPMVs in the three groups showed similar equilibrium transport rates, indicating similar vesicle sizes. The presence of the growing tumor resulted in a 40-120% increase in System y(+)-mediated arginine transport in HPMVs. This response was dependent on tumor size and was due to a stimulation of carrier Vmax, suggesting an increase in the number of functional System y+ carriers in the hepatocyte plasma membrane. The Na(+)-dependent transport of the System A analog MeAIB was also increased, but only in rats with large tumors.

Tumor growth results in a progressive increase in hepatic arginine transport, a response mediated primarily by an increase in the activity of System y+. This accelerated transport may amplify the availability of arginine to support key arginine-dependent metabolic pathways in the hepatocyte.