Inhibition of WY-14,643 induced hepatic lesion growth in mice by rotenone

Jason S. Isenberg, Kyle L. Kolaja, Siar A. Ayoubi, John B. Watkins, James E. Klaunig

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Abstract

The effect of rotenone treatment on [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio] acetic acid (WY-14,643) hepatic lesion growth in male B6C3F1 mice was investigated. Following induction of hepatic focal lesions by diethylnitrosamine (DEN) 35 mg/kg twice a week for 8 weeks, mice were placed into one of the four treatment groups: group I, control NIH-07 diet (control diet), group II, rotenone (600 mg/kg diet), group III NIH-07 diet containing WY-14,643 (1000 mg/kg diet), and group IV, NIH-07 diet containing WY-14,643 (1000 mg/kg diet) and rotenone (600 mg/kg diet). Mice were killed after 30 and 60 days of dietary treatment. The effect of treatment with WY-14,643 and rotenone on hepatic lesion growth was examined by estimating the number of focal lesions per liver and the relative volume of focal lesions. WY-14,643 (group III) increased both the number and the volume of focal lesions. In particular, an increase in number and volume of basophilic lesions was seen. Co-treatment with WY-14,643 and rotenone (group IV) decreased both the number and the volume of the total number of focal lesions and basophilic foci compared with WY-14,643 treatment alone (group II). Alterations in the growth of hepatic focal lesions was further investigated by examining DNA synthesis and apoptosis within individual lesions. WY-14,643 (group III) treatment increased the DNA synthetic labeling index in all foci. Co-treatment of rotenone and WY-14,643 (group IV) decreased focal DNA synthesis and mitosis and increased the incidence of apoptotic hepatocytes. These data suggest that rotenone's ability to inhibit WY-14,643-induced hepatic focal lesion growth was mediated through a decrease in hepatic focal proliferation and an increase in focal apoptosis.

Original languageEnglish (US)
Pages (from-to)1511-1519
Number of pages9
JournalCarcinogenesis
Volume18
Issue number8
DOIs
StatePublished - Aug 1 1997

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  • Cancer Research

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Isenberg, J. S., Kolaja, K. L., Ayoubi, S. A., Watkins, J. B., & Klaunig, J. E. (1997). Inhibition of WY-14,643 induced hepatic lesion growth in mice by rotenone. Carcinogenesis, 18(8), 1511-1519. https://doi.org/10.1093/carcin/18.8.1511