Inhibitory effects of quaternary ammonium compounds on lysosomal degradation of endogenous proteins.

The effects of quaternary ammonium compounds on the degradation of endogenous proteins in isolated lysosomes were studied. Proteolysis was assayed by measuring the trichloroacetic acid-soluble radioactivity in the lysosomes which had been labeled in vivo with 14C-leucine. p-Biphenylmethyl-(dl-tropyl-alpha-tropinium)bromide (BTTB), at concentrations higher than 0.85 mM, was found to inhibit the lysosomal proteolysis stoichiometrically. Other quaternary ammonium compounds, such as N-methylatropinium bromide (NMA), cetyltrimethylammonium bromide (CTAB), tubocurarine and gallamine, were also examined in the presence or absence of Triton X-100 which is able to destroy the lysosomal membranes. Of these four compounds, NMA was the most effective proteolysis inhibitor, showing 25% inhibition for intact lysosomes at a concentration of 1 mM of the compound. When these compounds were assayed after Triton X-100 treatment of the lysosomes, the effects of all the drugs were augmented, suggesting that they, after accumulation in the lysosomes, act through direct interactions with lysosomal proteases. This was supported by a kinetic analysis of the action of NMA on cathepsin B, a typical lysosomal protease.