       Document 0173
 DOCN  M9630173
 TI    Antiviral drugs from the nucleoside analog family block volume-activated
       chloride channels.
 DT    9603
 AU    Gschwentner M; Susanna A; Woll E; Ritter M; Nagl UO; Schmarda A; Laich
       A; Pinggera GM; Ellemunter H; Huemer H; et al; Department of Physiology,
       University of Innsbruck, Austria.
 SO    Mol Med. 1995 May;1(4):407-17. Unique Identifier : AIDSLINE MED/96091364
 AB    BACKGROUND: The antiviral drugs AZT and acyclovir are generally used in
       the treatment of infections with human immunodeficiency virus (HIV) and
       herpes simplex virus (HSV). These substances are known to impede virus
       replication by premature nucleic acid chain termination. It is not yet
       clear, however, if this is the sole mechanism responsible for the
       antiviral and/or the numerous side effects observed in patients treated
       with these agents. We investigated the swelling-induced chloride current
       in fibroblasts, which we demonstrated is closely related or identical to
       a cloned epithelial chloride channel, ICln: This chloride channel can be
       blocked by nucleotides. MATERIALS AND METHODS: Electrophysiological,
       fluorescence optical, and volume measurements were made to determine the
       effect of nucleoside analogs on the swelling-dependent chloride current
       (ICl) in NIH 3T3 fibroblasts and in human T cell lymphoma (H9) cells and
       the cAMP-dependent chloride current in CaCo cells. RESULTS: AZT and
       acyclovir block the swelling-dependent chloride current and the chloride
       flux in fibroblasts, and the regulatory volume decrease (RVD) and ICl in
       H9 cells. This immediate effect can be substantially reduced by the
       simultaneous incubation of the cells with thymidine-5'-diphosphate (TDP)
       or uridine, both of which are by themselves unable to affect ICl.
       CONCLUSIONS: We show here a novel molecular mechanism by which antiviral
       drugs of the nucleoside analog family could lead to impairments of the
       kidney, bone marrow, gastrointestinal, and neuronal functions, and how
       these side effects could possibly be restricted by the presence of TDP
       or uridine.
 DE    Acyclovir/*PHARMACOLOGY  Animal  Antiviral Agents/*PHARMACOLOGY  Cell
       Size  Chloride Channels/*ANTAGONISTS & INHIB  Human  Mice  Patch-Clamp
       Techniques  Support, Non-U.S. Gov't  Thymidine  Tumor Cells, Cultured
       Uridine  Zidovudine/*PHARMACOLOGY  3T3 Cells  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

