Induction of rat liver DNA alterations by chronic administration of peroxisome proliferators as detected by 32P-postlabeling

Erika Randerath*, Kurt Randerath, Ranjani Reddy, Tracy F. Danna, M. Sambasiva Rao, Janardan K. Reddy

*Corresponding author for this work

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

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 32P-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 32P-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 32P-postlabeling assay.

Original languageEnglish (US)
Pages (from-to)65-76
Number of pages12
JournalMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
Volume247
Issue number1
DOIs
StatePublished - Mar 1991

Keywords

  • DNA modifications
  • I-compounds, P-postlabelling
  • Non-mutagenic cariinogens
  • Peroxisome proliferators

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Health, Toxicology and Mutagenesis

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