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

Abstract

ABSTRACT: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 downregulated 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. Tolllike 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.

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

“…Several factors that regulate FMO transcription are known (33)(34)(35)(36)(37). 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).…”

Selective Modulation of Hepatic Cytochrome P450 and Flavin Monooxygenase 3 Expression duringCitrobacter rodentiumInfection in Severe Combined Immune-Deficient Mice

“…CR infection is associated with a profound down-regulation of mouse liver Cyp4a mRNA and protein expression, as well as of flavin monooxygenase 3 (Fmo3) in the liver Chaluvadi et al, 2009a;Zhang et al, 2009). Drug-metabolizing P450s of the Cyp3a gene subfamily, as well as Cyp2b9, are down-regulated to a lesser extent, whereas other 1-, 2-, and 3-family P450 enzymes are less affected and display some variability in response between experiments.…”

“…In B6 mice infected with CR, the time course or hepatic P450 up-or down-regulation correlates with that of colonic colonization, with a maximum at 7 to 10 days of infection and resolution of the responses by 15 days. Colonic hypertrophy persists until 15 days of infection, and the down-regulation of Fmo3 persists at least until 21 days (Zhang et al, 2009). Therefore, we chose the 7-day time point for the present study.…”

Pharmacokinetics of Morphine in Rats with Adjuvant-induced Arthritis

“…When LPS is administered to rats, the expression levels and activity of a flavin-containing monooxygenase decline, and this effect is restored by inhibiting nitric oxide (NO) synthase. Therefore, NO may be involved in regulating flavin-containing monooxygenase activity during inflammation (17). A reduction in the expression levels of UGT has also been reported, while inflammatory cytokines have been shown to reduce drugtransporter function in both animal and human cellular models (18).…”