Protein synthesis inhibition by 8-oxo-12,13-epoxytrichothecenes

• Published in: Biochimica et biophysica acta Vol. 923; no. 2; pp. 206 - 213
• Main Authors: Ehrlich, Kenneth C., Daigle, Kim W.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 20.02.1987; Elsevier; North-Holland
• Subjects: 4-deoxynivalenol; Biological and medical sciences; cell culture; Cells, Cultured; chemical synthesis; contamination; corn; drug effects; Fundamental and applied biological sciences. Psychology; inhibition; Mammalian cell culture; mammals; Molecular and cellular biology; Molecular genetics; mycotoxicosis; Mycotoxin; Peptide Biosynthesis; Peptide Chain Elongation, Translational; Peptide Chain Elongation, Translational - drug effects; Peptide Chain Initiation, Translational; Peptide Chain Initiation, Translational - drug effects; pharmacology; Polyribosomes; Polyribosomes - drug effects; Polysome; Protein Biosynthesis; protein synthesis; Protein synthesis inhibition; Sesquiterpenes; Sesquiterpenes - pharmacology; Spectrophotometry, Infrared; Structure-Activity Relationship; Translation. Translation factors. Protein processing; Trichothecene; trichothecenes; Trichothecenes - chemical synthesis; Trichothecenes - pharmacology; wheat; Mammalian cell culture; Mycotoxin; 4-DON; T-2 toxin; Polysome; Trichothecene; Protein synthesis inhibition; Cell culture; Translation; Inhibition; Tumor cell
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/0304-4165(87)90005-5

The Fusarium mycotoxin, 4-deoxynivalenol, is an abundant, natural contaminant of corn and wheat. 8-Oxo-12,13-epoxytrichothecenes related to 4-deoxynivalenol were synthesized; they either lacked the 7-hydroxyl but contained a hydroxyl at C-4 (7-deoxynivalenol) or lacked substituents at C-3 and C-7 (3,7-dideoxynivalenol). The ability of these synthetic analogs and their acetylated derivatives to inhibit protein synthesis by cultured mammalian cells was compared to that of 4-deoxynivalenol. Whereas the 50% inhibitory dose (ID50) for murine erythroleukemia cells was about 1 μg/ml for 4-deoxynivalenol and 3,7-dideoxynivalenol, all of the other analogs were at least 10-fold less potent. When tested at their ID50 dose, all of the 8-oxotrichothecenes, except 4-deoxynivalenol and 3,7-dideoxynivalenol, caused polysome ‘run-off’, indicating that, at this dose, they are inhibitors of polypeptide chain initiation. With 4-deoxynivalenol and 3,7-dideoxynivalenol, polysomes remained at control levels indicating that these toxins prevent polypeptide chain elongation. From these results and comparisons to previous studies of 8-oxo-12,13-epoxytrichothecenes (trichothecolone, trichothecin, nivalenol and fusarenone X), trichothecenes with substituents at both C-3 and C-4 predominantly inhibit polypeptide chain initiation, whereas those lacking one substituent at either site are inhibitors of chain elongation.