Selective inhibition of lysosomal protein degradation by the thiol proteinase inhibitors E-64, Ep-459 and Ep-457 in isolated rat hepatocytes.

The effects on protein degradation of the thiol proteinase inhibitor E-64 of fungal original, and its two synthetic analogs Ep-459 and Ep-475, were examined, using isolated rat hepatocytes. All three inhibitors were found to act selectively on lysosomal protein degradation. i.e., their effects were not additive to the lysosomotropic weak base propylamine. Such weak bases appear to be relatively complete and selective inhibitors of lysosomal protein degradation. Ep-475 and E-64 were found to be the most potent of the three, inhibiting as much as 50% of the total degradation (i.e., approx. 70% of the lysosomal degradation) at concentrations at which they did not disturb protein synthesis. Their lack of additivity to the lysosomotropic weak base propylamine further testifies to the usefulness of weak bases differentiating between lysosomal and non-lysosomal protein degradation.