Increased degradation in rat liver induced by vinblastine. I. Biochemical characterization.

The administration of vinblastine sulfate to rats causes an increase in degradation of liver proteins and lipids as measured in vitro by the release of trichloroacetic acid-soluble products. In mitochondrial-lysosomal fractions both lipolysis and proteolysis increase. Postmicrosomal supernatants (cytosol) also show an increase in lipolysis. Little or no enhancement of degradation occurs in the microsomal fraction. The stimulation of degradation by vinblastine is dose-related and is associated with increased lysosomal fragility. Degradation in vitro in the vinblastine model persists longer than in the control. No alterations either in the recovery of cell fractions or in the distribution of lysosomal enzymes are seen after vinblastine treatment. The increase in proteolysis induced by vinblastine can be completely prevented by pretreating the rats with either low or high doses of cycloheximide. Biochemical characterization by use of an inhibitor (iodoacetamide) of cathepsins and by use of ammonium chloride suggests that the increased proteolysis seen after vinblastine is related to increased sequestration of substrate into the lysosomal pool. Our studies do not support the notion that in the liver vinblastine impairs fusion between autophagosomes and preexisting primary or secondary lysosomes during the time points studied. The stimulation of both proteolysis and lipolysis in the liver lysosomes of rats treated with vinblastine provides an experimental model for the studies on mechanisms of intralysosomal degradation of cell constituents.