The thiol proteinase inhibitors,Z-Phe-PheCHN2 and Z-Phe-AlaCHN2, inhibit lysosomal protein degradation in isolated rat hepatocytes

The effects on protein metabolism of Z-Phe-PheCHN₂ and Z-Phe-AlaCHN₂ were examined in isolated rat hepatocytes. The two thiol proteinase inhibitors caused a drastic reduction in the degradation of both endogenous adn endocytosed (asialo-fetuin) protein. The inhibition was not additive to that of the lysosomotropic base methylamine, indicating that Z-Phe-PheCHN₂ and Z-Phe-AlaCHN₂ only affect lysosomal degradation. At high concentrations (0.1–1 mM) both inhibitors reduced protein synthesis strongly. This finding indicates non-specific/toxic effects, which may limit the usefulness of the inhibitors.