NAD depletion after in vitro exposure of murine lung slices to bleomycin

Biochem Pharmacol. 1993 Nov 17;46(10):1819-24. doi: 10.1016/0006-2952(93)90588-n.


Bleomycin (BLM), a DNA-cleaving, antitumor antibiotic, causes pulmonary fibrosis. It also causes cell injury and activates the nuclear enzyme poly(ADP-ribose) polymerase (PAP; EC in lung slices exposed to the drug in vitro. 3-Aminobenzamide (3-AB), a PAP inhibitor, prevents enzyme activation and cell injury. We have examined the potential role of ATP and NAD depletion in injury of BLM-sensitive C57B1/6N and -resistant BALB/cN murine lung slices treated with BLM or deprived of glucose, the major metabolic substrate of lung. Lung slices either were treated for 45 min with injurious concentrations of BLM (10-500 micrograms/mL) or were incubated without glucose, in the presence or absence of 2.5 mM 3-AB. Only the highest concentration of BLM, 500 micrograms/mL, caused any ATP depletion, and this 35% decrease was transient, occurring at 220 min in C57B1/6N slices. In contrast, glucose deprivation caused 50-70% ATP depletion in slices from both strains. BLM alone at 100 and 500 micrograms/mL caused a sustained 30-70% NAD depletion from 75 min through 400 min in C57B1/6N mouse lung slices. In the resistant BALB/cN lung slices, NAD depletion by BLM was only seen at 400 min. 3-AB almost completely antagonized NAD depletion in slices from both strains. In contrast to BLM, glucose deprivation did not decrease NAD levels unless 3-AB was present in C57B1/6N slices. Thus, ATP depletion may play a role in the injurious effects of glucose deprivation, but does not appear to be a major factor in pneumocyte injury caused by BLM. NAD depletion or other effects of PAP activation appear to account for the strain-selective, injurious effect of BLM on lung tissue.

Publication types

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

MeSH terms

  • Adenosine Triphosphate / analysis
  • Animals
  • Benzamides / pharmacology
  • Bleomycin / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Female
  • Glucose / deficiency
  • In Vitro Techniques
  • Lung / drug effects*
  • Lung / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • NAD / deficiency*
  • Poly(ADP-ribose) Polymerases
  • Time Factors


  • Benzamides
  • NAD
  • Bleomycin
  • 3-aminobenzamide
  • Adenosine Triphosphate
  • Poly(ADP-ribose) Polymerases
  • Glucose