Furan-induced liver cell proliferation and apoptosis in female B6C3F1 mice.
Furan is a potent rodent hepatocarcinogen that probably acts through non-genotoxic mechanisms involving hepatotoxicity and regenerative hepatocyte proliferation. In addition to inducing necrosis, cytotoxicants like furan may also induce cytolethality through apoptosis which has been suggested to play a key role in carcinogenesis. Hepatocyte proliferation and apoptosis were studied in female B6C3F1 mice exposed to furan by oral gavage for 3 weeks at National Toxicology Program (NTP) bioassay doses (8 and 15 mg/kg body weight) and lower (4 mg/kg). Furan treatment led to a 2- to 3-fold significant increase in liver-related enzymes and bile acids in blood serum as compared to the control group. These changes were accompanied by minor subcapsular inflammation and minimal necrosis at 8 and 15 mg furan/kg. A dose-related increase in bromodeoxyuridine-labeling index (1.4- to 1.7-fold) and hematoxylin- and eosin-defined apoptotic index (6- to 15-fold) was observed at 8 and 15 mg/kg. Co-treatment of mice with aminobenzotriazole, an irreversible inhibitor of cytochromes P-450, prevented the observed hepatotoxic effects induced by furan. These results indicate that furan elicits hepatotoxicity in a dose-related manner through a toxic metabolite and, furthermore, suggest that apoptosis is an important form of cell death at hepatocarinogenic doses under short-term conditions.
Fransson-Steen
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R
Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709, USA.
Goldsworthy
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TL
Kedderis
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GL
Maronpot
R R
RR
D000284:Administration, Oral; D000410:Alanine Transaminase / Q000097:blood; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001647:Bile Acids and Salts / Q000097:blood*; D001973:Bromodeoxyuridine / Q000737:chemistry; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005663:Furans / Q000008:administration & dosage / Q000633:toxicity*; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D009336:Necrosis
D001647:Bile Acids and Salts; D002273:Carcinogens; D005663:Furans; D007064:L-Iditol 2-Dehydrogenase; D000410:Alanine Transaminase; D001973:Bromodeoxyuridine; C039281:furan