       Document 0931
 DOCN  M9440931
 TI    Cardiac mitochondrial DNA polymerase-gamma is inhibited competitively
       and noncompetitively by phosphorylated zidovudine.
 DT    9404
 AU    Lewis W; Simpson JF; Meyer RR; Department of Pathology and Laboratory
       Medicine, University of; Cincinnati, College of Medicine, OH.
 SO    Circ Res. 1994 Feb;74(2):344-8. Unique Identifier : AIDSLINE
       MED/94123453
 AB    Zidovudine (azidothymidine [AZT]) inhibits human immunodeficiency virus
       replication and reduces the severity of acquired immunodeficiency
       syndrome. A limiting side effect of AZT is a mitochondrial cardiac and
       skeletal myopathy in which the pharmacologically active derivative of
       AZT (AZT triphosphate) plays a critical role. The present study
       determined biochemical mechanisms of AZT-induced mitochondrial toxicity
       and identified AZT triphosphate as an inhibitor of DNA polymerase-gamma
       in vitro. Inhibition kinetics were defined using purified bovine cardiac
       mitochondrial DNA polymerase-gamma and AZT triphosphate in vitro. The Km
       for deoxythymidine triphosphate was 0.8 +/- 0.3 mumol/L. AZT
       triphosphate incubation with DNA polymerase-gamma in vitro resulted in
       mixed kinetics with a competitive Ki of 1.8 +/- 0.2 mumol/L and a
       noncompetitive Ki' of 6.8 +/- 1.7 mumol/L. These Ki and Ki' values were
       strikingly higher than values for retroviral reverse transcriptase but
       lower than values for other cellular DNA polymerases. These data support
       previous molecular and morphological findings in clinical AZT
       mitochondrial myopathy and in models of AZT myopathy in vivo.
       Biochemical findings suggest that inhibition of mitochondrial DNA
       polymerase-gamma may be integral to the pathogenesis of AZT-induced
       myopathy.
 DE    Animal  Cattle  Comparative Study  DNA Polymerase III/*ANTAGONISTS &
       INHIB  Kinetics  Mitochondria, Heart/*ENZYMOLOGY  Phosphorylation
       Support, Non-U.S. Gov't  Support, U.S. Gov't, P.H.S.  Thymine
       Nucleotides/METABOLISM/PHARMACOLOGY  Zidovudine/ANALOGS &
       DERIVATIVES/*PHARMACOLOGY  JOURNAL ARTICLE

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

