Evidence that swainsonine pretreatment of rats leads to the formation of autophagic vacuoles and endosomes with decreased capacity to mature to, or fuse with, active lysosomes.
The plant toxin swainsonine causes a variety of biochemical and morphological changes in animal tissues. In rat liver there is an extensive vacuolization which is not accompanied by an accumulation of oligosaccharide. In investigating this proliferation of autophagic vacuoles we have found that swainsonine administration leads to a shift in the density of liver lysosomes as indicated by the distribution of several lysosomal glycosidases in sucrose gradients. Whereas most of these activities are normally found in low density fractions, only a minor portion occurring in high density fractions, the reverse distribution is observed after the administration of microgram doses of swainsonine. Two promoters of the accumulation of autophagic vacuoles, vinblastine and chloroquine, caused the expected increase in very light vacuoles as measured by localization of two acid hydrolases. However, this effect of the two agents was blocked by swainsonine pretreatment. Moreover, swainsonine decreased the degradation of endocytosed asialofetuin and increased the retention of the glycoprotein in very light fractions. These results suggest that vesicle movement and/or fusion is inhibited by the pretreatment with the toxin. That the effects are mediated by a change in vacuolar membrane is suggested by the finding that lysosomes prepared from the livers of swainsonine-fed rats are much more fragile than control lysosomes, more so in metrizamide solutions than in sucrose solutions. The swainsonine may exert its effect through its known ability to alter the biosynthesis of complex glycoproteins, which are abundant and distinctive in lysosomal membranes.
Tulsiani
D R
DR
Department of Molecular Biology, Vanderbilt University, Nashville, Tennessee 37235.
Touster
O
O
D000818:Animals; D001212:Asialoglycoproteins / Q000378:metabolism; D002458:Cell Fractionation; D002499:Centrifugation, Density Gradient; D002738:Chloroquine / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects; D060748:Fetuins; D008099:Liver / Q000187:drug effects / Q000648:ultrastructure*; D008247:Lysosomes / Q000187:drug effects* / Q000648:ultrastructure; D008297:Male; D008793:Metrizamide / Q000494:pharmacology; D009994:Osmolar Concentration; D051381:Rats; D011919:Rats, Inbred Strains; D012996:Solutions; D013395:Sucrose / Q000494:pharmacology; D017026:Swainsonine / Q000494:pharmacology*; D014617:Vacuoles / Q000187:drug effects* / Q000648:ultrastructure; D014747:Vinblastine / Q000494:pharmacology; D000509:alpha-Fetoproteins / Q000378:metabolism
D001212:Asialoglycoproteins; D060748:Fetuins; D012996:Solutions; D000509:alpha-Fetoproteins; C017029:asialofetuin; D013395:Sucrose; D014747:Vinblastine; D002738:Chloroquine; D008793:Metrizamide; D017026:Swainsonine