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Mechanistic Study on Hepatocarcinogenesis of Piperonyl Butoxide in Mice
1 Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo 183-8509, Japan Correspondence: Kunitoshi Mitsumori, D.V.M., Ph.D., Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan; e-mail:mitsumor{at}cc.tuat.ac.jp.
To clarify the mechanism of piperonyl butoxide (PBO)-induced hepatocarcinogenesis in mice, male mice were subjected to a two-thirds partial hepatectomy, N-diethylnitrosamine (DEN) initiation, and a diet containing 0.6% PBO for eight weeks. The incidence of
Key Words: PBO • ROS • ATF3 • liver • oxidative stress Abbreviations: ABC, streptavidin-biotin peroxidase complex • Abcc2, ATP-binding cassette, sub-family C (CFTR/MRP), member 2 • Abcc3, ATP-binding cassette, sub-family C (CFTR/MRP), member 3 • Abcc4, ATP-binding cassette, sub-family C (CFTR/MRP), member 4 • Actb, actin, beta, cytoplasmic • AhR, aryl-hydrocarbon receptor • ATF2, activating transcription factor 2 • ATF3, activating transcription factor 3 • CAR, nuclear receptor subfamily 1, group I, member 3 • c-fos, mus musculus FBJ osteosarcoma oncogene • c-Jun, Jun oncogene • c-Myc, myelocytomatosis oncogene • CT, cycle time • CYP, cytochrome P450 • Cyp1a1, cytochrome P450, family 1, subfamily a, polypeptide 1 • Cyp2a5, cytochrome P450, family 2, subfamily a, polypeptide 5 • Cyp2b9, cytochrome P450, family 2, subfamily b, polypepetide 9 • Cyp2b10, musculus cytochrome P450, 2b10, phenobarbital inducible, type b • DAB, 3,3'-diaminobenzidine • DCFH-DA, 2',7'-dichlorodihydrofluorescein diacetate • DEN, N-diethylnitrosamine • GGT,
This version was published on October
1, 2009 Toxicologic Pathology, Vol. 37, No. 6,
761-769 (2009) |
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-glutamyl transpeptidase (GGT)-positive foci and PCNA-positive cells was significantly increased in the DEN + PBO group compared with the DEN-alone group. Real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis showed up-regulation of genes related to metabolism, such as cytochrome P450 1A1 and 2B10, and metabolic stress, such as Por, Nqo1, Nrf2, abcc3, and abcc4. Early responsive genes downstream of mitogen-activated protein kinase (MAPK), such as c-fos, c-jun, c-myc, and activating transcription factor 3 (ATF3), were also up-regulated in this group. Positive immunohistochemical staining for ATF3 was diffusely observed in nonproliferating hepatocytes of the DEN + PBO group, but altered foci were negative or weakly positive for ATF3. The nuclei of hepatocytes within ATF3-negative foci were positive for cyclin D. Thus PBO can induce oxidative stress, activate the MAPK pathway, and increase ATF3 transcript levels in hepatocytes outside the altered foci during the early stage of PBO-induced hepatocarcinogenesis in mice.