Induction of rat liver DNA alterations by chronic administration of peroxisome proliferators as detected by 32P-postlabeling
| Autor: | Tracy F. Danna, M. Sambasiva Rao, Ranjani Reddy, Kurt Randerath, Janardan K. Reddy, Erika Randerath |
|---|---|
| Rok vydání: | 1991 |
| Předmět: |
Male
Health Toxicology and Mutagenesis Microbodies Clofibric Acid chemistry.chemical_compound Oral administration DNA adduct Genetics medicine Animals Molecular Biology Carcinogen Hypolipidemic Agents Nuclease biology Peroxisome proliferator Liver Neoplasms Fibric Acids Affinity Labels DNA Neoplasm Molecular biology Rats Inbred F344 Rats Pyrimidines Liver Biochemistry Mechanism of action chemistry biology.protein Ciprofibrate medicine.symptom DNA DNA Damage Mutagens medicine.drug |
| Zdroj: | Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis. 247:65-76 |
| ISSN: | 0027-5107 |
| DOI: | 10.1016/0027-5107(91)90034-l |
| Popis: | The mechanisms of the hepatocarcinogenicity of non-mutagenic peroxisome proliferators, i.e. compounds used as hypolipidemic drugs and industrial plasticizers, are not sufficiently understood. To gain more information on the mechanism of their action, the chronic effects of two structurally diverse peroxisome proliferators on rat-liver DNA were investigated by the 32 P-postlabeling assay. Male F-344 rats (1.5 month old) were fed ciprofibrate (0.025%) in the diet for 2, 5, 8, and 16 months or Wy-14643 (0.1%) for 18 months. Liver DNA from individual treated animals (3–4 per group) and age-matched controls was analyzed by the nuclease P1/bisphosphate version of the 32 P-postlabeling assay. Three distinct types of exposure-related DNA alterations were observed: (i) A significant reduction of the age-dependent accumulation of I-compounds (putative indigenous DNA modifications) (type 1), (ii) adduct-like DNA derivatives induced by the treatments (type 2), and (iii) as yet structurally uncharacterized radiolabeled material occupying substantial areas of DNA adduct maps and accumulating in an exposure time-dependent manner (type 3). DNA from liver tumors generated by these agents displayed only traces of I-compounds, lacked all but one adduct-like derivatives, and had no type 3 alterations. Thus, in contrast to the non-mutagenicity of peroxisome proliferators in short-term assays, chronic administration of these compounds led to DNA alterations that were detectable by 32 P-postlabeling assay. |
| Databáze: | OpenAIRE |
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