Modulation of base hydroxylation by bile acids and salicylates in a model of human colonic mucosal DNA: putative implications in colonic cancer

Dig Dis Sci. 1999 Apr;44(4):761-7. doi: 10.1023/a:1026670027150.


Bile acids are believed to be involved in the formation of colonic cancer, and 5-aminosalicylic acid and other salicylates may have a protective role. The precise mechanisms of both actions are not known, but modifications (stimulation or inhibition) of basal or oxygen-radical induced DNA base hydroxylation as potential early events in tumor formation by these compounds may be involved in such actions. We, therefore, investigated whether: (1) bile acids in concentrations as they occur systemically or intraluminally are able to enhance basal or OH*-radical-stimulated base hydroxylation in DNA from calf thymus; (2) 5-aminosalicylic acid, its main intestinal metabolite N-acetyl-aminosalicylic acid and salicylate, the main aspirin metabolite, are able to inhibit this hydroxylation; and (3) DNA from calf thymus can be used as a model by comparing its base composition and hydroxylation with DNA from normal human colonic mucosa. We found an enhancement of the OH*-radical-induced DNA hydroxylation especially 8-OH adenine with 214.0%. On the other hand 5-ASA, N-acetyl-ASA, and salicylate showed a concentration-dependent inhibition of OH*-stimulated hydroxylation with IC50 between 0.04 +/- 0.01 mM (X +/- SD) and 1.3 +/- 0.1 mM. No effects were observed on basal hydroxylation. Electron spin resonance spectroscopy studies showed reduction of the corresponding base signals pointing to a scavenger mechanism. In DNA isolated from normal human colonic mucosa (N = 7) a similar base distribution was found as in calf thymus; hydroxylation was < or = 1.0% in both systems. From our results we conclude that DNA from calf thymus may serve as a model for human colonic mucosal DNA and that one of the carcinogenic actions of bile acids may be enhancement of oxygen-radical-induced DNA base hydroxylation, especially 8-OH adenine. The absence of effects under unstimulated conditions supports their role as cocarcinogens. The concentration-dependent inhibition of OH*-stimulated DNA hydroxylation by 5-ASA, salicylate, and N-acetyl-ASA may be a possible mechanism of chemoprevention.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Bile Acids and Salts / pharmacology*
  • Cattle
  • Colonic Neoplasms / prevention & control
  • DNA / drug effects*
  • DNA / metabolism
  • Electron Spin Resonance Spectroscopy
  • Gas Chromatography-Mass Spectrometry
  • Gastrointestinal Agents / pharmacology*
  • Humans
  • Hydroxylation / drug effects
  • Inhibitory Concentration 50
  • Intestinal Mucosa / drug effects*
  • Salicylates / pharmacology*
  • Thymus Gland / drug effects*


  • Anti-Inflammatory Agents, Non-Steroidal
  • Bile Acids and Salts
  • Gastrointestinal Agents
  • Salicylates
  • DNA