The effect of fenbuconazole on cell proliferation and enzyme induction in the liver of female CD1 mice.
Fenbuconazole, a triazole fungicide, has been associated with an increase in the incidence of liver adenomas in female mice following long-term dietary exposure. The aim of this study was to evaluate whether the mode of action for liver tumor formation by fenbuconazole is similar to that of phenobarbital. Treatment of CD1 mice with 0, 20, 60, 180 or 1300 ppm fenbuconazole for up to 4 weeks caused a dose-dependent increase in liver weight that was associated with centrilobular hepatocellular hypertrophy, cytoplasmic eosinophilia and panlobular hepatocellular vacuolation, as well as an initial increase in the cell proliferation labeling index. Fenbuconazole also caused a dose-dependent increase in liver microsomal cytochromes b(5) and P450 and the levels of immunoreactive CYP2B10 and its associated activity 7-pentoxyresorufin O-dealkylation (PROD). Treatment of mice with 1000 ppm phenobarbital elicited the same effects as treatment of mice with 1300 ppm fenbuconazole, except that phenobarbital was more effective than fenbuconazole at inducing PROD activity, even though fenbuconazole induced CYP2B10 to the same extent as did phenobarbital. This difference was attributed to the ability of fenbuconazole to bind tightly to CYP2B10 and partially mask its catalytic activity in liver microsomes, which is characteristic of several azole-containing drugs. All hepatocellular changes and induced enzyme activity returned to control levels within 4 weeks of discontinuing treatment with fenbuconazole or phenobarbital, indicating that the observed changes were fully reversible. We conclude that fenbuconazole is a phenobarbital-type inducer of mouse liver cytochrome P450, and the mode of action by which fenbuconazole induces liver adenomas in mice is similar to that of phenobarbital.
Juberg
Daland R
DR
Human Health Assessment, Regulatory Laboratories, Dow AgroSciences, LLC 9330 Zionsville Road, Indianapolis, IN 46268, USA. drjuberg@dow.com
Mudra
Daniel R
DR
Hazelton
George A
GA
Parkinson
Andrew
A
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D049108:Cell Enlargement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D015786:Cytochromes b5 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects*; D005260:Female; D005659:Fungicides, Industrial / Q000008:administration & dosage / Q000633:toxicity; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000378:metabolism; D051379:Mice; D009570:Nitriles / Q000008:administration & dosage / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D010634:Phenobarbital / Q000008:administration & dosage / Q000633:toxicity; D013250:Steroid Hydroxylases / Q000378:metabolism; D013997:Time Factors; D014230:Triazoles / Q000008:administration & dosage / Q000633:toxicity*
D005659:Fungicides, Industrial; D009570:Nitriles; D014230:Triazoles; D015786:Cytochromes b5; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C101679:Cyp2b10 protein, mouse; D019362:Cytochrome P-450 CYP2B1; D000072467:Cytochrome P450 Family 2; C504383:fenbuconazole; D010634:Phenobarbital