Alkaloids from the poisonous plant Ipomoea carnea: effects on intracellular lysosomal glycosidase activities in human lymphoblast cultures.
There is natural intoxication of livestock by the ingestion of Ipomoea carnea (Convolvulaceae) in Brazil and other parts of the world. The alkaloidal glycosidase inhibitors swainsonine, 2-epi-lentiginosine, and calystegines B(1), B(2), B(3), and C(1) have been identified as constituents of this plant. Swainsonine is a potent inhibitor of rat lysosomal alpha-mannosidase, with an IC(50) value of 0.02 microM, whereas calystegines B(1), B(2), and C(1) are potent inhibitors of rat lysosomal beta-glucosidase, with IC(50) values of 2.1, 0.75, and 0.84 microM, respectively. The action of swainsonine results in a lysosomal storage disorder that closely mimics alpha-mannosidosis in humans. To determine whether the toxicity of I. carnea to livestock is due to purely swainsonine or due to a combination of effects by swainsonine and calystegines, intracellular lysosomal glycosidase activities in normal human lymphoblasts grown with inhibitors in the medium were examined. Incubation of lymphoblasts with 0.1 microM swainsonine for 3 days resulted in approximately 60% reduction of alpha-mannosidase activity. On the other hand, calystegines B(2) and C(1) showed no inhibition of beta-glucosidase up to 1 mM; instead inclusion of calystegines B(2) and C(1) at 100 microM in the culture medium increased its activity by 1.5- and 1.6-fold, respectively. Calystegines B(2) and C(1) seem to act as chemical chaperones, enhancing correct folding of the enzyme and enabling smooth trafficking to the lysosome. The lysosomal beta-glucosidase inhibitory calystegines seem to have little risk of inducing intoxication of livestock.
Ikeda
Kyoko
K
Faculty of Pharmaceutical Sciences, Hokuriku University, Ho-3 Kanagawa-machi, Kanazawa 920-1181, Japan.
Kato
Atsushi
A
Adachi
Isao
I
Haraguchi
Mitsue
M
Asano
Naoki
N
D000470:Alkaloids / Q000494:pharmacology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors*; D006801:Humans; D027741:Ipomoea / Q000737:chemistry*; D008214:Lymphocytes / Q000648:ultrastructure*; D008247:Lysosomes / Q000201:enzymology*; D009662:Nortropanes / Q000494:pharmacology; D012991:Solanaceous Alkaloids; D017026:Swainsonine / Q000494:pharmacology
D000470:Alkaloids; D004791:Enzyme Inhibitors; D009662:Nortropanes; D012991:Solanaceous Alkaloids; C110566:calystegine C1; C095613:calystegine B(2); D006026:Glycoside Hydrolases; D017026:Swainsonine