Elsevier

Biochemical Pharmacology

Volume 36, Issue 18, 15 September 1987, Pages 2945-2950
Biochemical Pharmacology

Phosphorolytic cleavage of 2-fluoroadenine from 9-β-d-arabinofuranosyl-2-fluoroadenine by Escherichia coli: A pathway for 2-fluoro-atp production☆

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Abstract

2-Fluoroadenine (F-Ade) is a metabolite of 9-β-D-arabinofuranosyl-2-fluoroadenine (F-ara-A) that may be involved in the development of toxic side effects from this anticancer drug. The liberation of F-Ade from F-ara-A has been examined in different biological systems. Extracts of Escherichia coli but not mammalian cells or tissues catalyzed the conversion of F-ara-A to F-Ade with apparent Km and Vmax values of 1350 μM and 7.7 nmol/min/mg protein respectively. This reaction depended on the presence of phosphate and was inhibited by purine nucleosides in a competitive manner, indicating that the enzyme responsible for the conversion is purine nucleoside phosphorylase. After incubation of intact bacteria with 100 μM [3H]F-ara-A, [3H]F-Ade was the same percentage of cellular radioactivity as in the medium, but it was only one-tenth the concentration of F-ara-A in the cells. In contrast, the cellular concentration of 2-fluoro-ATP was 20-fold greater than that of F-ara-A-5'-triphosphate. These results suggest that F-ara-A entered the bacteria intact and was phosphorolytically cleaved to liberate F-Ade, which would have been either anabolized to the toxic triphosphate or excreted. The latter pathway would provide a route by which F-Ade might be absorbed into the host circulation.

References (39)

  • R.W. Brockman et al.

    Biochem. Pharmac.

    (1977)
  • D. Spriggs et al.

    Biochem. Pharmac.

    (1986)
  • J.J. Kavanagh et al.

    Eur. J. Cancer clin. Oncol.

    (1985)
  • R.F. Struck et al.

    Biochem. Pharmac.

    (1982)
  • V. Avramis et al.

    Biochem. biophys. Res. Commun.

    (1983)
  • M.M. Bradford

    Analyt. Biochem.

    (1976)
  • G.J. McGarrity et al.

    Expl. Cell Res.

    (1982)
  • J. Hochstadt-Ozer

    J. biol. Chem.

    (1972)
  • A. Munch-Petersen et al.

    J. biol. Chem.

    (1979)
  • W. Plunkett et al.

    Cancer Res.

    (1980)
  • L.W. Dow et al.

    Cancer Res.

    (1980)
  • V.I. Avramis et al.

    Cancer Res.

    (1982)
  • W-C. Tseng et al.

    Molec. Pharmac.

    (1982)
  • E.L. White et al.

    Cancer Res.

    (1982)
  • W. Plunkett et al.
  • P. Huang et al.
  • J.A. Montgomery et al.

    J. med. Chem.

    (1969)
  • J.J. Brink et al.

    Cancer Res.

    (1964)
  • G.A. LePage et al.

    Drug Metab. Dispos.

    (1973)

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    ☆

    This work was supported by American Cancer Society Grant CH-130 and Grant CA28596 from the National Can- cer Institute, DHHS.

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