Inhibition of system A amino acid transport and hepatocyte proliferation following partial hepatectomy in the rat

System A, the sodium-dependent neutral amino acid transport activity, has a 3-fold increase in its initial uptake velocity into hepatocytes following partial hepatectomy (PH) in the rat. The purpose of this study was to exami ne the effect of inhibition of System A-mediated amino acid transport on he patocyte proliferation and liver regeneration. We describe the in vivo comp etitive inhibition of System A activity following PH by the nonmetabolizabl e, System A-specific substrate, alpha-(methylamino)isobutyric acid (MeAIB), Administration of MeAIB 60 minutes before PH decreased the incorporation o f [H-3]thymidine into DNA by 45% +/- 5% and 76% +/- 17% at 24 and 36 hours, respectively. The readministration of MeAIB every 12 hours further decreas ed DNA synthesis by 92% +/- 18% and 82% +/- 11% at 24 and 36 hours. The rec overy of liver mass of rats receiving MeAIB was decreased by 46.4% +/- 5.1% at 24 hours after PH. In vitro, 5 mmol/L MeAIB inhibited proliferation of primary hepatocytes by 56% +/- 4% and 61% +/- 12% 48 hours after incubation with 10% fetal calf serum or epidermal growth factor (5 ng/mL), respective ly. Thus, MeAIB inhibition of System A transport activity decreased both in vivo and in vitro inducement of hepatocyte proliferation. Treatment with M eAIB did not significantly change the incorporation of [H-3]leucine into to tal liver protein, but changes in serum amino acids and hepatocyte cell vol ume were observed, suggesting System A transport activity during hepatocyte proliferation functions primarily to provide amino acids to fuel liver-spe cific biochemical pathways and to increase cell volume.