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Mechanisms of toxicity of 3'-azido-3'-deoxythymidine. Its interaction with adenylate kinase.
- Source :
-
Biochemical pharmacology [Biochem Pharmacol] 1994 Oct 07; Vol. 48 (7), pp. 1405-12. - Publication Year :
- 1994
-
Abstract
- Recent experiments from our laboratory have indicated that the inhibitory effect of 3'-azido-3'-deoxythymidine (AZT) on oxidative phosphorylation may occur directly, in addition to being brought about by its inhibition of mtDNA replication. We report here studies on the effect of AZT on adenylate kinase, an enzyme crucial to oxidative phosphorylation. AZT decreased the aromatic residues fluorescence of rabbit muscle adenylate kinase, indicating binding of AZT to the enzyme. Of three other enzymes studied as controls, AZT bound only to those that possessed ATP/ADP binding sites. Up to concentrations of 15 microM, AZT was a more potent effector of fluorescence quenching than were ATP, ADP, AMP, and the AZT control, deoxythymidine. AZT strongly inhibited adenylate kinase in the direction of ATP synthesis (Ki, 8 microM), the inhibition being of the partial competitive type, whereas deoxythymidine inhibition, also partially competitive, was much weaker (Ki, 90 microM). When measured in the direction of ADP synthesis, AZT failed to demonstrate any inhibition at concentrations up to 10 microM. Experiments on isolated intact rat liver mitochondria with the enzyme activity measured in both directions confirmed the isolated enzyme results. Respiratory control by these mitochondria was not affected by AZT. The finding of AZT affinity for ATP/ADP binding sites may open new avenues of approach to the study of AZT toxicity.
- Subjects :
- Adenosine Diphosphate biosynthesis
Adenosine Triphosphate biosynthesis
Adenylate Kinase antagonists & inhibitors
Adenylate Kinase isolation & purification
Animals
Binding Sites
Dose-Response Relationship, Drug
Male
Mitochondria, Liver enzymology
Oxidative Phosphorylation drug effects
Oxygen Consumption drug effects
Rabbits
Rats
Rats, Wistar
Spectrometry, Fluorescence
Adenylate Kinase metabolism
Mitochondria, Liver drug effects
Zidovudine toxicity
Subjects
Details
- Language :
- English
- ISSN :
- 0006-2952
- Volume :
- 48
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Biochemical pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 7945440
- Full Text :
- https://doi.org/10.1016/0006-2952(94)90564-9