Effect of ten thiocompounds on rat liver DNA damage induced by a small dose of N-nitrosodimethylamine.
The use in a chemoprevention study of high doses of the genotoxic agent might result in erroneous information because of possible nonlinearity of pharmacokinetic processes and toxicity-induced derangement of physiological defense mechanisms. According to these premises ten thiocompounds, potentially active as inhibitors of metabolic activation and/or scavengers, were examined for their capability of reducing the frequency of liver DNA lesions induced by a very small dose of N-nitrosodimethylamine (NDMA). This was accomplished by means of a viscometric technique previously found suitable to detect a minimal amount of DNA fragmentation. Rats were injected i.p. or i.v. with 1 mmol/kg of thiocompound, 0.2 mg/kg NDMA given by gavage 1 h afterwards, and killed for DNA damage assessment 14 h later. Statistically significant changes of viscometric parameters, which are considered indicative of a protective activity, were produced by disulfiram (DSF), and to a lower extent by diethyldithiocarbamate (DEDTC). Any modification of NDMA-induced DNA damage was absent in rats pretreated with glutathione reduced form (GSH) and dimethyl sulfoxide (DMSO). Allyl disulfide (ADS), L-cysteine (CYS), N-acetylcysteine (NAC), alpha-mercaptopropionylglycine (MPG), ethylxanthic acid (PEX), and 2-mercaptoethane sulfonic acid (MESNA) increased in various degree the frequency of DNA-strand breaks. In subsequent experiments the protective activity of DSF was found to be dose-related, dependent on the time of administration, and greater by oral route. Taken as a whole, these results suggest that several putative anticarcinogens might be ineffective against the DNA-damage produced by the low doses encountered in human exposure.
Brambilla
G
G
Institute of Pharmacology, University of Genoa, Italy.
Carlo
P
P
Finollo
R
R
D000284:Administration, Oral; D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D004128:Dimethylnitrosamine / Q000037:antagonists & inhibitors*; D016166:Free Radical Scavengers; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013455:Sulfur / Q000494:pharmacology*; D014783:Viscosity
D016166:Free Radical Scavengers; D013455:Sulfur; D004128:Dimethylnitrosamine