Phosphorylation of the anti-hepatitis B nucleoside analog 1-(2'-deoxy-2'-fluoro-1-beta-D-arabinofuranosyl)-5-iodouracil (FIAU) by human cytosolic and mitochondrial thymidine kinase and implications for cytotoxicity

Antimicrob Agents Chemother. 1996 Jun;40(6):1555-7. doi: 10.1128/AAC.40.6.1555.

Abstract

The capacity of recombinant human cytosolic thymidine kinase (TK1) and bovine mitochondrial thymidine kinase (TK2) to phosphorylate the antiviral analogs 1-(2'-deoxy-2'-fluoro-1-beta-D-arabinofuranosyl)-5-iodouracil (FIAU) and 1-(2'-deoxy-2'-fluoro-1-beta-D-arabinofuranosyl)-5-methyluracil (FMAU) has been analyzed. The Vmax/Km ratios for FIAU and FMAU with TK2 are about 30% of that for deoxythymidine, while the corresponding values for TK1 are 2 and 5%, respectively. Thus, these two analogs are more efficient substrates for TK2 than for TK1, which may be part of the explanation for the mitochondrial toxicity associated with FIAU during treatment of hepatitis B infection.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / metabolism*
  • Antiviral Agents / toxicity
  • Arabinofuranosyluracil / analogs & derivatives*
  • Arabinofuranosyluracil / metabolism
  • Arabinofuranosyluracil / toxicity
  • Cattle
  • Cells, Cultured
  • Cytosol / enzymology
  • Humans
  • Mitochondria / enzymology
  • Phosphorylation
  • Substrate Specificity
  • Thymidine Kinase / isolation & purification
  • Thymidine Kinase / metabolism*

Substances

  • Antiviral Agents
  • Arabinofuranosyluracil
  • fialuridine
  • Thymidine Kinase
  • clevudine