3'-Azidothymidine (zidovudine) inhibits glycosylation and dramatically alters glycosphingolipid synthesis in whole cells at clinically relevant concentrations

Recent in vitro work with Golgi-enriched membranes showed that 3'-azidothymidine-5'-monophosphate (AZTMP), the primary intracellular metabolite of 3'-azidothymidine (AZT), is a potent inhibitor of glycosylation reactions (Hall et al. (1994) J. Biol. Chem. 269, 14355-14358) and predict...

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Bibliographic Details
Published in:The Journal of biological chemistry 1995-09, Vol.270 (39), p.22836-22841
Main Authors: Yan, J P, Ilsley, D D, Frohlick, C, Steet, R, Hall, E T, Kuchta, R D, Melançon, P
Format: Article
Language:English
Subjects:
Carbohydrate Conformation
Carbohydrate Sequence
Cell Line
DNA Replication - drug effects
Dose-Response Relationship, Drug
Galactose - metabolism
Glycosphingolipids - biosynthesis
Glycosphingolipids - chemistry
Glycosylation - drug effects
Golgi Apparatus - drug effects
Golgi Apparatus - metabolism
Hexosamines - metabolism
Humans
Kinetics
Leukemia, Erythroblastic, Acute
Molecular Sequence Data
Radioisotope Dilution Technique
Reverse Transcriptase Inhibitors - pharmacology
Structure-Activity Relationship
Tritium
Tumor Cells, Cultured
Zidovudine - analogs & derivatives
Zidovudine - metabolism
Zidovudine - pharmacology
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Summary:Recent in vitro work with Golgi-enriched membranes showed that 3'-azidothymidine-5'-monophosphate (AZTMP), the primary intracellular metabolite of 3'-azidothymidine (AZT), is a potent inhibitor of glycosylation reactions (Hall et al. (1994) J. Biol. Chem. 269, 14355-14358) and predicted that AZT treatment of whole cells should cause similar inhibition. In this report, we verify this prediction by showing that treatment of K562 cells with AZT inhibits lipid and protein glycosylation. AZT treatment dramatically alters the pattern of glycosphingolipid biosynthesis, nearly abolishing ganglioside synthesis at clinically relevant concentrations (1-5 microM), and suppresses the incorporation of both sialic acid and galactose into proteins. Control experiments demonstrate that these changes do not result from nonspecific effects on either the secretory apparatus or protein synthesis. On the other hand, studies using isolated nuclei as a model system for chromosomal DNA replication show that AZTTP is a very weak inhibitor of DNA synthesis. These observations strongly suggest that the myelosuppressive effects of AZT in vivo are due to inhibition of protein and/or lipid glycosylation and not to effects on chromosomal DNA replication.
ISSN:0021-9258
DOI:10.1074/jbc.270.39.22836