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ToxSci Advance Access published online on December 2, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfh031
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received July 29, 2003; accepted October 22, 2003
© 2003 Society of Toxicology

Carcinogenicity

Prevention by Methionine of Dichloroacetic Acid-Induced Liver Cancer and DNA Hypomethylation in Mice

Michael A. Pereira 1*, Wei Wang 1, Paula M. Kramer 1, and Lianhui Tao 1

1 Department of Pathology, Medical College of Ohio, 3055 Arlington Avenue, Toledo, Ohio 43614-5806, USA

* To whom correspondence should be addressed. E-mail: pereira.25{at}osu.edu.


  Abstract

Dichloroacetic acid (DCA) is a liver carcinogen that induces DNA hypomethylation in mouse liver. To test the involvement of DNA hypomethylation in the carcinogenic activity of DCA, we determined the effect of methionine on both activities. Female B6C3F1 mice were administered 3.2g/l DCA in their drinking water and 0, 4.0 and 8.0g/kg methionine added to their diet. Mice were sacrificed after 8 and 44 weeks of exposure. After 8 weeks of exposure, DCA increased the liver/body weight ratio and caused DNA hypomethylation, glycogen accumulation and peroxisome proliferation. Methionine prevented completely the DNA hypomethylation, reduced by only 25% the glycogen accumulation and did not alter the increased liver/body weight ratio and the proliferation of peroxisomes induced by DCA. After 44 weeks of exposure, DCA induced foci of altered hepatocytes and hepatocellular adenomas. The multiplicity of foci of altered hepatocytes/mouse was increased from 2.41 ± 0.38 to 3.40 ± 0.46 by 4.0g/kg methionine and decreased to 0.94 ± 0.24 by 8.0g/kg methionine suggesting that methionine slowed the progression of foci to tumors. The low and high concentrations of methionine reduced the multiplicity of liver tumors/mouse from 1.28 ± 0.31 to 0.167 ± 0.093 and 0.028 ± 0.028, i.e. by 87 and 98%, respectively. Thus, the prevention of liver tumors by methionine was associated with its prevention of DNA hypomethylation indicating that DNA hypomethylation was critical for the carcinogenic activity of DCA.

Key Words: Chemoprevention, dichloroacetic acid, DNA hypomethylation, methionine, mouse liver tumors, prevention of cancer .


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