ToxSci Advance Access published online on December 16, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl188
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Orphan Nuclear Receptor Constitutive Active/Androstane Receptor (CAR)-mediated Alterations in DNA Methylation during Phenobarbital (PB) Promotion of Liver Tumorigenesis
CAR-MEDIATED ALTERED DNA METHYLATION
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* Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824
Laboratorie of Reproductive and Developmental Toxicology, North Carolina 27709
Laboratorie of Experimental Pathology, NIEHS, NIH, Research Triangle Park, North Carolina 27709
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan 48824
1 Corresponding Author: Jay I. Goodman, Michigan State University, B-440 Life Sciences Bldg., East Lansing, MI 48824, Email: goodman3{at}msu.edu, Tel: 517-353-9346, Fax: 517-353-8915
Received October 26, 2006; accepted December 12, 2006
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Abstract |
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Altered DNA methylation is an epigenetic mechanism that plays a key role in the carcinogenesis process, and the nongenotoxic rodent hepatocarcinogen phenobarbital (PB) alters the methylation status of DNA in mouse liver. The constitutive active/androstane nuclear receptor (CAR) mediates half of the PB-induced hepatic gene expression changes and it is essential for liver tumor promotion in PB-treated mice. Here, a technique involving methylation-sensitive restriction digestion, arbitrarily primed PCR, and capillary electrophoresis was utilized to detect PB-induced regions of altered DNA methylation (RAMs) in CAR wildtype (WT) mice that are sensitive to promotion by PB and resistant CAR knockout (KO) mice. The CAR WT mice developed preneoplastic lesions after 23 wk of PB treatment (precancerous) and liver tumors after 32 wk, while the CAR KO mice did not develop tumors (Yamamoto et al., 2004). Our goal was to discern those RAMs which are playing important roles in tumor formation by comparing the RAMs that form in sensitive and resistant groups of mice. Using this novel approach, 42 unique RAMs were identified in the precancerous as compared to the CAR KO, 23 wk PB-treated tissue. Of these 42 RAMs, 14 carried forward to the tumor tissue, and additionally, 104 total unique RAMs were observed in the tumor tissue. These results indicate that there are unique RAMs occurring in the sensitive CAR WT mice and that a portion of these are seen in both the precancerous and tumor tissue. We hypothesize that these unique RAMs may be facilitating the tumorigenesis process, and these data support the view that DNA methylation plays a causative role in PB-induced tumorigenesis.
Key Words: CAR; DNA methylation; mouse liver; phenobarbital; tumors.
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