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Drug Metabolism and Disposition Fast Forward
First published on September 2, 2008; DOI: 10.1124/dmd.108.023457

0090-9556/08/3612-2499-2505$20.00
DMD 36:2499-2505, 2008

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Aryl Hydrocarbon Receptor-Dependent Induction of Flavin-Containing Monooxygenase mRNAs in Mouse LiverFormula

Trine Celius, Steven Roblin, Patricia A. Harper, Jason Matthews, Paul C. Boutros, Raimo Pohjanvirta, and Allan B. Okey

Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada (T.C., S.R., P.A.H., J.M., P.C.B., A.B.O.); Research Institute, the Hospital for Sick Children, Toronto, Ontario, Canada (S.R., P.A.H.); and Department of Food and Environmental Hygiene, University of Helsinki, Helsinki, Finland (R.P.); and National Public Health Institute, Laboratory of Toxicology, Kuopio, Finland (R.P.)

Flavin-containing monooxygenases (FMOs) are important in detoxication but generally are considered not to be inducible by xenobiotics. Our recent microarray studies revealed induction of FMO2 and FMO3 mRNAs by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in liver of mice with wild-type aryl hydrocarbon receptor (AHR) but not in Ahr-null mice. The aim of the present study was to delineate mechanisms of FMO regulation. In adult male mice, basal FMO3 mRNA is low but was induced 6-fold at 4 h and 6000-fold at 24 h. The ED50 was approximately 1 µg/kg for FMO2 and FMO3, similar to that for the classic AHR-regulated gene, Cyp1a1. In adult female mice basal FMO3 mRNA is high and was not induced at 4 h but was elevated 8-fold at 24 h. FMO5 mRNA was significantly down-regulated by TCDD in both male and female adult mice. Juvenile mice show no sex difference in response to TCDD; FMO3 was induced 4 to 6-fold by TCDD in both sexes. Chromatin immunoprecipitation demonstrated recruitment of AHR and aryl hydrocarbon nuclear translocator proteins to Fmo3 regulatory regions, suggesting that induction by TCDD is a primary AHR-mediated event. Although FMO2 and FMO3 mRNAs were highly induced by TCDD in adult males, overall FMO catalytic activity increased only modestly. In contrast to the striking up-regulation of FMO2 and FMO3 in mouse liver, TCDD has little effect on FMO mRNA in rat liver. However, FMO2 and FMO3 mRNAs were highly induced in transgenic mice that express wild-type rat AHR, indicating that lack of induction in rat is not due to an incompetent AHR in this species.

Address correspondence to: Dr. Allan B. Okey, Department of Pharmacology and Toxicology, Medical Sciences Building, 1 King's College Circle, University of Toronto, Toronto, ON, Canada M5S 1A8. E-mail: allan.okey{at}utoronto.ca




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