Quantitative relationship of lysosomal glycogen accumulation to lysosomal alpha-glucosidase inhibition in castanospermine-treated rats.
To quantitatively examine the relationship between lysosomal acid alpha-glucosidase (LAAG, alpha-D-glucoside glucohydrolase, EC 3.2.1.20) inhibition and glycogen accumulation, rats were treated with castanospermine (CS), and liver lysosomal/mitochondrial fractions were analyzed for glycogen content and LAAG activity. Liver lysosomal glycogen accumulation positively correlated (r = 0.90) with the amount of LAAG inhibition when inhibition was about 50% or greater. Glycogen did not accumulate when LAAG inhibition was less than 50%. The route of CS administration had little effect on the amount of LAAG inhibition observed. In rats killed 17 hr after CS administration, the doses estimated to cause 50% LAAG inhibition were 0.77, 0.11, and 0.22 mg/kg for i.p., i.v., and oral administration respectively. After 89% inhibition of LAAG activity with a single oral dose of 10 mg CS/kg, LAAG activity returned to 50% of normal value in about 2.5 days. Accumulated glycogen disappeared as LAAG activity recovered. Surprisingly, twelve daily CS doses of 1 mg/kg had only a small cumulative effect on LAAG inhibition and did not cause more glycogen accumulation than a single dose.
Rhinehart
B L
BL
Merrell Dow Research Institute, Cincinnati, OH 45215.
Begovic
M E
ME
Robinson
K M
KM
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight; D004305:Dose-Response Relationship, Drug; D006003:Glycogen / Q000378:metabolism*; D065089:Glycoside Hydrolase Inhibitors; D007212:Indolizines; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008247:Lysosomes / Q000378:metabolism*; D051381:Rats; D013997:Time Factors; D054836:Indolizidines
D000470:Alkaloids; D006003:Glycogen; D065089:Glycoside Hydrolase Inhibitors; D007212:Indolizines; C037806:castanospermine; D054836:Indolizidines