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Effect of peroxisome proliferators on the methylation and protein level of the c‐ myc protooncogene in B6C3F1 mice liver
Author(s) -
Ge Rongrong,
Tao Lianhui,
Kramer Paula M.,
Cunningham Michael L.,
Pereira Michael A.
Publication year - 2002
Publication title -
journal of biochemical and molecular toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.526
H-Index - 58
eISSN - 1099-0461
pISSN - 1095-6670
DOI - 10.1002/jbt.10019
Subject(s) - gemfibrozil , dna methylation , methylation , carcinogen , medicine , endocrinology , biology , gene expression , phthalate , peroxisome proliferator activated receptor , tumor promotion , chemistry , microbiology and biotechnology , biochemistry , gene , carcinogenesis , cholesterol , organic chemistry
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. © 2002 Wiley Periodicals, Inc. J Biochem Mol Toxicol 16:41–47, 2002; DOI 10.1002/jbt.10019