Metabolism of arabinosyladenine in herpes simplex virus-infected and uninfected cells: Correlation with inhibition of DNA synthesis and role in antiviral selectivity

The metabolism of 9-β- D-arabinofuranosyladenine (ara-A, vidarabine) and its effects on DNA synthesis were compared in uninfected and herpes simplex virus type-1 (HSV-1)-infected KB cells. In the absence of an inhibitor of adenosine deaminase, ara-A was deaminated to 9-β- D-arabinofuranosylhypoxanth...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Biochemical pharmacology 1984-08, Vol.33 (15), p.2431-2438
Hauptverfasser: Schwartz, Pauline M., Novack, Jean, Shipman, Charles, Drach, John C.
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung:The metabolism of 9-β- D-arabinofuranosyladenine (ara-A, vidarabine) and its effects on DNA synthesis were compared in uninfected and herpes simplex virus type-1 (HSV-1)-infected KB cells. In the absence of an inhibitor of adenosine deaminase, ara-A was deaminated to 9-β- D-arabinofuranosylhypoxanthine and phosphorylated to ara-A-5′-mono-, di- and triphosphates in both types of cells. When an inhibitor of adenosine deaminase (coformycin) was added to cell cultures, nucleotides were the only metabolites detected—primarily the 5′-triphosphate of ara-A (aATP). Detailed studies performed in the presence of coformycin established that the net rate and extent of aATP formation were the same in uninfected and HSV-1-infected cells. After a 12-hr exposure to 50 μM ara-A, intracellular concentrations of aATP were approximately 40 μM. Levels of aATP correlated directly with inhibition of total DNA synthesis. Approximately 0.7 μM aATP was required for 50% inhibition of total DNA synthesis in both uninfected and HSV-1-infected cells. Following removal of ara-A-containing culture medium, aATP levels in uninfected cells declined with a half-life of 3.2 hr. In marked contrast, the half-life in HSV-1-infected cells was 9.3 hr; this may explain why as little as a 3-hr exposure to ara-A resulted in a significant HSV-1 titer reduction. Taken together, the data show that when ara-A was removed from culture medium, levels of aATP persisted longer in HSV-1-infected cells thereby prolonging antiviral activity. This effect could be important in vivo where levels of ara-A oscillate with dosing schedule.
ISSN:0006-2952
1873-2968
DOI:10.1016/0006-2952(84)90715-9