Disturbances in DNA precursor metabolism associated with exposure to an inhibitor of poly(ADP-ribose) synthetase

Exp Cell Res. 1986 Jul;165(1):260-8. doi: 10.1016/0014-4827(86)90550-1.

Abstract

3-Aminobenzamide (3AB) is widely used as an inhibitor of poly(ADP-ribose) synthetase to study the effect of protein ribosylation on various cellular processes, but the specificity of its inhibition has not been demonstrated. We found that 3AB has a wide range of effects on DNA precursor metabolism, as determined by high-performance liquid chromatographic separation of deoxynucleosides derived from enzymatic digestion of cellular DNA. 3AB (10-20 mM) significantly reduced cell growth in human lymphoblastoid cells. Furthermore, the incorporation of [3H]deoxycytidine into DNA was significantly enhanced relative to incorporation of [3H]deoxythymidine, [3H]deoxyguanosine, and [3H]deoxyadenosine. Incorporation of fragments of [3H]glucose into the pyrimidine fraction of DNA was significantly inhibited relative to incorporation into the purine fraction. At only 1 mM, 3AB had a major inhibitory effect on the incorporation of the methyl group from [3H]methionine into deoxyguanosine, deoxyadenosine, and deoxycytidine, with 50% inhibition into deoxyguanosine and deoxyadenosine and 90% inhibition into deoxycytidine. The specificity of 3AB inhibition to poly(ADP-ribose) synthetase is therefore doubtful in view of this variety of metabolic effects, involving pyrimidine synthesis and de novo synthesis via the one-carbon pool.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Benzamides / pharmacology*
  • Chromatography, High Pressure Liquid
  • DNA / biosynthesis
  • Deoxyadenosines / metabolism
  • Deoxycytidine / metabolism
  • Deoxyguanosine / metabolism
  • Humans
  • Nucleosides / metabolism*
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Thymidine / metabolism

Substances

  • Benzamides
  • Deoxyadenosines
  • Nucleosides
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Deoxycytidine
  • 3-aminobenzamide
  • DNA
  • Deoxyguanosine
  • Thymidine