Hepatic Expression of Polymerase β, Ref-1, PCNA, and Bax in WY 14,643-Exposed Rats and Hamsters
| Autor: | Earle W. Holmes, M.L. Cunningham, C.M. Bingham |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Male
medicine.medical_specialty Time Factors Carbon-Oxygen Lyases Immunoblotting Clinical Biochemistry Hamster Mitochondrion Biology Cell Fractionation medicine.disease_cause Pathology and Forensic Medicine Rats Sprague-Dawley Cricetinae Proliferating Cell Nuclear Antigen Proto-Oncogene Proteins Internal medicine DNA-(Apurinic or Apyrimidinic Site) Lyase medicine Animals Molecular Biology DNA Polymerase beta bcl-2-Associated X Protein Endodeoxyribonucleases Dose-Response Relationship Drug medicine.disease Rats Proliferating cell nuclear antigen Pyrimidines medicine.anatomical_structure Endocrinology Liver Proto-Oncogene Proteins c-bcl-2 Apoptosis Hepatocyte Hepatocellular carcinoma biology.protein Peroxisome Proliferators Carcinogenesis Oxidative stress |
| Zdroj: | Experimental and Molecular Pathology. 73:209-219 |
| ISSN: | 0014-4800 |
| Popis: | The hepatic levels of three protein markers of oxidative stress, polymerase beta, Ref-1, and PCNA, and of the pro-apoptotic protein, Bax, were quantitated after exposure to WY 14,643 (500 ppm in the feed) for 6 or 34 days in a rodent that is susceptible peroxisome proliferator (PP)-induced liver tumors (the Sprague Dawley rat) and in a rodent that is relatively resistant PP-induced liver tumors (the Syrian hamster). The analysis of detergent-extracted whole liver homogenates by immunoblotting showed a marked increase in the abundance of a 45-kDa variant of polymerase beta immunoreactivity and significant increases in the expression of Ref-1 and PCNA in WY 14,643-exposed rats. In contrast. WY 14,643-exposed hamsters expressed only trace levels of the polymerase beta variant and showed significant decreases in the expression of Ref-1 and PCNA. Long-term WY 14,643 exposure was associated with marked decreases in Bax expression in both species. Dose-response studies in the rat showed that the hepatic expression of the polymerase beta and Ref-1 were significantly increased after 6 days of exposure to WY 14,643 at levels of 5 and 50 ppm, respectively. The analysis of subcellular fractions of rat liver showed that the pathological increases in the levels of polymerase beta, Ref-1, and PCNA were especially prominent in mitochondria-enriched particulate liver subfractions. These results indicate that WY 14,643 exposure is associated with an increase in oxidative stress to the liver and that liver mitochondria are a major target of WY 14,643-associated liver damage. Our data are consistent with the hypothesis that the chronic overexpression of mutagenic or oncogenic effectors like polymerase beta and Ref-1 in a setting of increased hepatocyte proliferation and decreased apoptosis may facilitate peroxisome proliferator-induced hepatocellular carcinoma in the rat. |
| Databáze: | OpenAIRE |
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