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-beta-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-beta-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 microM ara-A, intracellular concentrations of aATP were approximately 40 microM. Levels of aATP correlated directly with inhibition of total DNA synthesis. Approximately 0.7 microM 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.
D001089:Arabinose / Q000031:analogs & derivatives / Q000378:metabolism; D003070:Coformycin / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis*; D003641:Deamination; D006561:Herpes Simplex / Q000378:metabolism*; D006801:Humans; D009303:Nasopharyngeal Neoplasms; D010428:Pentosephosphates; D010766:Phosphorylation; D018139:Simplexvirus / Q000187:drug effects; D014740:Vidarabine / Q000378:metabolism* / Q000494:pharmacology; D014776:Virus Cultivation; D014779:Virus Replication / Q000187:drug effects
D010428:Pentosephosphates; D003070:Coformycin; C025444:arabinose 5-triphosphate; D004247:DNA; D001089:Arabinose; D014740:Vidarabine