Effects on in vivo and in vitro administration of vinblastine on the perfused rat liver--identification of crinosomes.

Livers of nonstarved rats were perfused for up to 4 hr in a recirculating system. Bile production, transaminases, and the lactate/pyruvate ratio remained at normal values. The ultrastructure of the hepatocytes was also well preserved even after the 4-hr perfusion. When vinblastine was given either in vivo or in vitro by addition to the perfusion fluid, it caused a conspicuous expansion of the autophagic-lysosomal compartment. Initially, nascent autophagic vacuoles developed, followed by the appearance of more mature ones and finally an increase in dense bodies was observed. In addition, administration of vinblastine in vivo gave rise to an increased occurrence of a subpopulation of lysosomes laden with VLDL-like particles. The term crinosomes seems appropriate for these lysosomal vesicles, since they apparently evolve by means of fusion between retained secretory granules and preexisting lysosomes (dense bodies). Addition of vinblastine of the perfusion fluid decreased the rate of proteolysis whether four times the serum concentration of amino acids were added or not. However, when vinblastine was given in vivo, proteolysis as measured in the perfusate decreased during the initial 3 hr of VBL treatment, whereas by longer times of pretreatment protein degradation exceeded the control value, constituting an example of catch-up proteolysis. Autophagic vacuoles isolated after short exposure to vinblastine in vivo exhibited high rates of protein degradation when incubated at acid pH. Insufficient proton pumping rather than lack of hydrolytic enzymes seems to be the most plausible explanation for this prompt pH effect.