3'-Azido-3'-deoxythymidine potently inhibits protein glycosylation. A novel mechanism for AZT cytotoxicity

• Published in: The Journal of biological chemistry Vol. 269; no. 20; pp. 14355 - 14358
• Main Authors: HALL, E. T, JIAN-PING YAN, MELANCON, P, KUCHTA, R. D
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Biochemistry and Molecular Biology 20.05.1994
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; CHO Cells; Cricetinae; Cytidine Monophosphate N-Acetylneuraminic Acid - metabolism; Dideoxynucleotides; Glycosylation - drug effects; Golgi Apparatus - metabolism; HIV - drug effects; HIV Infections - drug therapy; Humans; Intracellular Membranes - metabolism; Kinetics; Medical sciences; Membrane Proteins - metabolism; Nucleoside Diphosphate Sugars - metabolism; Pharmacology. Drug treatments; Protein Processing, Post-Translational - drug effects; Thymine Nucleotides - toxicity; Uridine Diphosphate Galactose - metabolism; Uridine Diphosphate N-Acetylglucosamine - metabolism; Zidovudine - analogs & derivatives; Zidovudine - metabolism; Zidovudine - therapeutic use; Zidovudine - toxicity; Intracellular transport; Rodentia; Retroviridae; Cytotoxicity; Glycosylation; Golgi apparatus; Virus; Ovary; Vertebrata; Mammalia; Antiviral; Lentivirinae; Carbohydrate; Human immunodeficiency virus; Hamster
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/S0021-9258(17)36627-9

3'-Azido-3'-deoxythymidine (AZT) is one of the primary chemotherapeutic agents used in the treatment of human immunodeficiency virus (HIV) infection. Unfortunately, AZT therapy is accompanied by severe side effects. Using Golgi-enriched membrane fractions, we have determined that 3'-azido-3'-deoxythymidine monophosphate, the primary AZT metabolite in treated cells, potently inhibits protein glycosylation. This inhibition results from direct competition with several pyrimidine-sugars for transport into Golgi membranes. This potential mechanism of cytotoxicity does not involve 3'-azido-3'-deoxythymidine triphosphate, the AZT metabolite most likely responsible for its antiviral effects; thus, it may be possible to develop novel therapeutic strategies that prevent inhibition of glycosylation without affecting the anti-HIV properties of AZT.