Potential chemoprotectant activity of mechanism-based glycosidase inhibitors against ricin toxicity in Chinese hamster ovary and macrophage J774A.1 cell cultures.
The abilities of the triacetylated galacto- and gluco-derivatives of 2-deoxy-2-fluoro-D-pyranosyl fluoride as well as alpha- and beta-N-bromoacetyl-D-galactopyranosylamine to inhibit the cytotoxicity of ricin in vitro in macrophage J774A.1 and Chinese hamster ovary (CHO) cell lines were determined. Leakage of lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) from the cells into the culture media were used as indicators of ricin cytotoxicity. The potential chemoprotectants were used in concentrations ranging from 10(-8) to 10(-4) g ml-1. Of the four potential mechanism-based, site-specific glycosidase inhibitors that were tested, 3,4,6-tri-O-acetyl-2-deoxy-2-fluoro- beta-D-glucopyranosyl fluoride exhibited the greatest chemoprotectant activity. The ricin-induced LDH release was inhibited in a concentration-dependent manner by this compound, with the LDH leakage returning to control values in the presence of the highest concentration of this chemoprotectant in both cell cultures when given 4 h prior to ricin. This compound exhibited a small but significant inhibition of AST release from both cell cultures when given simultaneously with ricin. 3,4,6-Tri-O-acetyl-2-deoxy-2-fluoro-beta-D-galactopyranosyl fluoride exhibited a small but significant chemoprotective effect only at the highest concentration in both cell cultures when given simultaneously with ricin. Both the alpha- and beta-isomers of N-bromoacetyl-D-galactopyranosylamine exhibited activity against ricin toxicity in the CHO cell line, with the beta-isomer exhibiting greatest activity. The beta-isomer exhibited greater cytotoxicity in the absence of ricin, as demonstrated by the release of both enzymes from the cultured CHO cells. Further studies will be required to assess the utility of these compounds as chemoprotectants against ricin toxicity in vivo.
Hassoun
E A
EA
School of Pharmacy and Allied Health Professions, Creighton University, Omaha, NE 68178, USA.
Bagchi
D
D
Roche
V F
VF
Stohs
S J
SJ
D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005688:Galactosamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D005947:Glucose / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology; D012276:Ricin / Q000037:antagonists & inhibitors* / Q000633:toxicity*
D004791:Enzyme Inhibitors; D005688:Galactosamine; D012276:Ricin; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D006026:Glycoside Hydrolases; D005947:Glucose