ISSN:
1573-2568
Keywords:
BASE HYDROXYLATION
;
BILE ACIDS
;
AMINOSALICYLIC ACID
;
N-ACETYL-AMINOSALICYLIC
;
SALICYLATE
;
CHEMOPREVENTION
;
COLON CANCER
;
INFLAMMATORY BOWEL DISEASE
;
COLONIC DNA MODEL
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract Bile acids are believed to be involved in theformation of colonic cancer, and 5-aminosalicylic acidand other salicylates may have a protective role. Theprecise mechanisms of both actions are not known, but modifications (stimulation or inhibition)of basal or oxygen-radical induced DNA basehydroxylation as potential early events in tumorformation by these compounds may be involved in suchactions. We, therefore, investigated whether: (1) bile acidsin concentrations as they occur systemically orintraluminally are able to enhance basal orOH-radical-stimulated base hydroxylation in DNA fromcalf thymus; (2) 5-aminosalicylic acid, its main intestinalmetabolite N -acetyl-aminosalicylic acid and salicylate,the main aspirin metabolite, are able to inhibit thishydroxylation; and (3) DNA from calf thymus can be used as a model by comparing its basecomposition and hydroxylation with DNA from normal humancolonic mucosa. We found an enhancement of theOH-radical-induced DNA hydroxylation especially 8-OH adenine with 214.0%. On the other hand 5-ASA,N -acetylASA, and salicylate showed aconcentration-dependent inhibition of OH-stimulatedhydroxylation with IC50 between 0.04 ±0.01 mM (X ± SD) and 1.3 ± 0.1 mM. No effects were observed onbasal hydroxylation. Electron spin resonancespectroscopy studies showed reduction of thecorresponding base signals pointing to a scavengermechanism. In DNA isolated from normal human colonic mucosa (N =7) a similar base distribution was found as in calfthymus; hydroxylation was 1.0% in both systems. From ourresults we conclude that DNA from calf thymus may serve as a model for human colonic mucosalDNA and that one of the carcinogenic actions of bileacids may be enhancement of oxygen-radical-induced DNAbase hydroxylation, especially 8-OH adenine. The absence of effects under unstimulatedconditions supports their role as cocarcinogens. Theconcentration-dependent inhibition of OH-stimulated DNAhydroxylation by 5-ASA, salicylate, and N-acetyl-ASA may be a possible mechanism ofchemoprevention.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1026670027150
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