Inhibition of WY-14,643 induced hepatic lesion growth in mice by rotenone.
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.
Isenberg
J S
JS
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis 46202, USA.
Kolaja
K L
KL
Ayoubi
S A
SA
Watkins
J B
JB
Klaunig
J E
JE
D000236:Adenoma / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001973:Bromodeoxyuridine / Q000032:analysis; D002273:Carcinogens / Q000037:antagonists & inhibitors*; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D004052:Diethylnitrosamine; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008830:Microbodies / Q000187:drug effects / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010084:Oxidation-Reduction / Q000187:drug effects; D011743:Pyrimidines / Q000037:antagonists & inhibitors*; D012402:Rotenone / Q000494:pharmacology*
D002273:Carcinogens; D011743:Pyrimidines; D012402:Rotenone; D004052:Diethylnitrosamine; C006253:pirinixic acid; D004247:DNA; D001973:Bromodeoxyuridine