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Drug Metabolism and Disposition Fast Forward
First published on December 16, 2008; DOI: 10.1124/dmd.108.025338

0090-9556/09/3703-462-468$20.00
DMD 37:462-468, 2009

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Hepatic Flavin-Containing Monooxygenase Gene Regulation in Different Mouse Inflammation ModelsFormula

Jun Zhang, Madhusudana R. Chaluvadi, Rob Reddy, Meike S. Motika, Terrilyn A. Richardson, John R. Cashman, and Edward T. Morgan

Human BioMolecular Research Institute, San Diego, California (J.Z., R.R., M.S.M., J.R.C.); and Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia (M.R.C., T.A.R., E.T.M.)

The objective of the study was to investigate the regulation of hepatic flavin-containing monooxygenases (Fmo) Fmo1, Fmo3, Fmo4, and Fmo5 in three different mouse models of inflammation, including treatment with Citrobacter rodentium, lipopolysaccharide (LPS), and dextran sulfate sodium (DSS). Quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) was used to evaluate the steady-state mRNA levels for the various Fmo isoforms in these mouse models of inflammation during different treatment time courses. Fmo3 mRNA was most significantly down-regulated in C. rodentium-treated female mice. Fmo1, Fmo3, and Fmo5 mRNAs were also found to be down-regulated in LPS models of inflammation. The significant down-regulation of hepatic FMO3 protein during C. rodentium treatment was confirmed with Western blot analysis of liver microsomes from treated animals. Toll-like receptor (TLR) 4 is known to be responsible for LPS signaling in association with several proteins. To investigate whether TLR4 was responsible for regulation of Fmo genes in both LPS and C. rodentium animal models, Fmo mRNA levels in female wild-type (C3H/HeOuJ) and TLR4 mutant (C3H/HeJ) mice were compared in both inflammatory models by real-time RT-PCR. The results showed that Fmo3 down-regulation during C. rodentium infection is independent of TLR4. Whereas TLR4 is likely to play only a partial role in Fmo1 gene regulation in LPS-treated animals, our results show that the down-regulation of Fmo3 and Fmo5 in this model is TLR4-dependent. Unlike cytochrome P450 regulation measured in the same mouse strains, Fmo3 expression was largely refractory to down-regulation in the DSS model of inflammatory colitis.

Address correspondence to: Edward Morgan, Emory University School of Medicine, 5119 Rollins Research Center, 1510 Clifton Road, Atlanta, GA 30322. E-mail: etmorga{at}emory.edu




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