title: Effect of peroxisome proliferators on the methylation and protein level of the c-myc protooncogene in B6C3F1 mice liver.
abstract: Peroxisome proliferators in general are nongenotoxic mouse liver carcinogens for which DNA hypomethylation and altered gene expression are proposed mechanisms. Therefore, the peroxisome proliferators 2,4-dichlorophenoxyacetic acid (2,4-D), dibutyl phthalate (DBP), gemfibrozil, and Wy-14,643 were evaluated for the ability to alter the methylation and expression of the c-myc protooncogene. Male B6C3F1 mice were administered for 6 days in their diet Wy-14,643 (5-500 ppm), 2,4-D (1,680 ppm), DBP (20,000 ppm), or gemfibrozil (8,000 ppm). All four peroxisome proliferators caused hypomethylation of the c-myc gene in the liver. Wy-14,643 appeared to be the most efficacious with a threshold between 10 and 50 ppm. The level of the c-myc protein was increased by Wy-14,643, but not the other peroxisome proliferators. When female B6C3F1 mice received a two-thirds partially hepatectomy and 16 h later were administered 50 mg/kg Wy-14,643 by gavage, hypomethylation of the gene occurred 24 h later. Hypomethylation was not found in mice that received Wy-14,643 following a sham operation. Hypomethylation of the c-myc gene within 24 h of administering Wy-14,643 after a partial hepatectomy but not after a sham operation supports the hypothesis that the peroxisome proliferators prevent methylation of hemimethylated sites formed by DNA replication.
authors.affiliation: Department of Pathology, Medical College of Ohio, Toledo, OH 43614-5806, USA.
authors.forename: Rongrong
authors.initials: R
authors.lastname: Ge
authors.forename: Lianhui
authors.initials: L
authors.lastname: Tao
authors.forename: Paula M
authors.initials: PM
authors.lastname: Kramer
authors.forename: Michael L
authors.initials: ML
authors.lastname: Cunningham
authors.forename: Michael A
authors.initials: MA
authors.lastname: Pereira
mesh_terms: D000284:Administration, Oral; D000818:Animals; D015153:Blotting, Western; D019175:DNA Methylation / Q000187:drug effects*; D016259:Genes, myc / Q000187:drug effects*; D006498:Hepatectomy; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D020025:Peroxisome Proliferators / Q000633:toxicity*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis*
chemical_list: D020025:Peroxisome Proliferators; D016271:Proto-Oncogene Proteins c-myc