Carcinogenesis, Vol 18, 1511-1519, Copyright © 1997 by Oxford University Press
JS Isenberg, KL Kolaja, SA Ayoubi, JB Watkins 3rd and JE Klaunig
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.
ARTICLES
Inhibition of WY-14,643 induced hepatic lesion growth in mice by rotenone
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis 46202, USA.
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