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

Abstract

ABSTRACT: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 g/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 downregulated 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.

Lipopolysaccharide-Induced Epithelial Monoamine Oxidase Mediates Alveolar Bone Loss in a Rat Chronic Wound Model

“…Fmo1 is generally thought to be uninducible by xenobiotics, although recently it was reported to be up-regulated via the aryl hydrocarbon receptor. 31 Maob has previously been found to be inducible by 17␤-estradiol in hamster kidney preceding carcinogenesis. 32 Flavin-containing monooxygenase 1 protein expression did not show any significant change at the protein level in either PLE culture or rat histological sections and so was not further studied (data not shown).…”

Differential Localization of Flavin-Containing Monooxygenase (FMO) Isoforms 1, 3, and 4 in Rat Liver and Kidney and Evidence for Expression of FMO4 in Mouse, Rat, and Human Liver and Kidney Microsomes

“…Little is known about how FMO zonation is regulated and whether it is modified with endogenous or exogenous signals. FMO expression is affected by testosterone and estrogen exposure (Falls et al, 1997) and by foreign compounds such as 2,3,7,8,-tetrachlorodibenzo-p-dioxin, 3-methylchlorathane, and ranitidine (Chung et al, 1997;Rae et al, 2001;Tijet et al, 2006;Celius et al, 2008). It is noteworthy that individual P450s respond to inducers in the rat liver acinus in a region-dependent manner, generally being induced in the same area that the isozyme is constitutively expressed (Bü hler et al, 1992).…”

Flavin-containing monooxygenases in aging and disease: Emerging roles for ancient enzymes

“…Estrogen (29) and insulin (34) activate FMO transcription, whereas testosterone (29) and glucagon (37) are repressors of FMO transcription, but FMO5 is again an exception (38). Several hormone receptors have been placed both upstream and downstream of FMOs (39,40). Large differences can exist between FMO mRNA abundance, FMO protein levels, and FMO functional activity (39,41,42), indicating multiple levels of regulation that require further study.…”

“…Several hormone receptors have been placed both upstream and downstream of FMOs (39,40). Large differences can exist between FMO mRNA abundance, FMO protein levels, and FMO functional activity (39,41,42), indicating multiple levels of regulation that require further study.…”