Regulation of Hepatic Cytochrome P450 Expression in Mice with Intestinal or Systemic Infections ofCitrobacter rodentium

Abstract

ABSTRACT:We reported previously that infection of C3H/HeOuJ (HeOu) mice with the murine intestinal pathogen Citrobacter rodentium caused a selective modulation of hepatic cytochrome P450 (P450) gene expression in the liver that was independent of the Toll-like receptor 4. However, HeOu mice are much more sensitive to the pathogenic effects of C. rodentium infection, and the P450 down-regulation was associated with significant morbidity in the animals. Here, we report that oral infection of C57BL/6 mice with C. rodentium, which produced only mild clinical signs and symptoms, produced very similar effects on hepatic P450 expression in this strain. As in HeOu mice, CYP4A mRNAs and proteins were among the most sensitive to down-regulation, whereas CYP4F18 was induced. CYP2D9 mRNA was also induced 8-to 9-fold in the C57BL/6 mice. The time course of P450 regulation followed that of colonic inflammation and bacterial colonization, peaking at 7 to 10 days after infection and returning to normal at 15 to 24 days as the infection resolved. These changes also correlated with the time course of significant elevations in the serum of the proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor-␣, as well as of interferon-␥ and IL-2, with serum levels of IL-6 being markedly higher than those of the other cytokines. Intraperitoneal administration of C. rodentium produced a rapid down-regulation of P450 enzymes that was quantitatively and qualitatively different from that of oral infection, although CYP2D9 was induced in both models, suggesting that the effects of oral infection on the liver are not due to bacterial translocation.

Effect of Lipopolysaccharide on the Xenobiotic-Induced Expression and Activity of Hepatic Cytochrome P450 in Mice

“…Disease states, such as bacterial infection, 31) rheumatoid arthritis, 32) and cancer, 33) lead to fluctuations in Cyp gene expressions and the enzyme activities of their products. Here we sought to examine the mechanisms underlying the fluctuations in Cyp gene expressions under an inflammatory physiological state, using LPS-treated mice as a model of inflammation.…”

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

“…Fmo3 mRNA was the most significantly decreased Fmo isoform after C. rodentium infection. The gradual recovery of Fmo3 mRNA in the C. rodentium-treated mouse was noticeably slower than what we observed previously for P450 mRNAs, most of which were back to normal at 15 days (Chaluvadi et al, 2008a). Even at day 24 when bacterial infection was completely cleared and no pathological symptoms were apparent for these animals, the levels of Fmo3 mRNA (13%) and protein (36%) were still far from normal.…”

“…It is interesting that the down-regulation of Fmo3 was much more profound in the C57BL/6 strain, one that showed less pathogenesis, than in the HeOu mice. This was not true of the most profoundly down-regulated P450 studied, the CYP4As, which were more affected in the HeOu mice (Richardson and Morgan, 2005;Chaluvadi et al, 2008a). These results suggest that regulatory factors distinct from that involved in P450 regulation are required for the down-regulation of Fmo3 during infection and the restoration of Fmo3 transcription post-C. rodentium infection of mice.…”

“…In the C. rodentium model, down-regulation of Fmo1 mRNA correlated well with the time course of bacterial colonization of the colon, which was significant at 7 days postinfection, reached its peak at 10 days, and then declined to negligible counts at days 15 and 24 (Chaluvadi et al, 2008a). This temporal profile is similar to that of the regulation of many P450 mRNAs studied in these same mice, as well as of the plasma profile of cytokine including interleukin-6, tumor necrosis factor-␣, and interferon-␥ (Chaluvadi et al, 2008a). The Fmo1 protein level followed the same time course as the down-regulation of mRNA, indicating a pretranslational physiologically relevant regulation.…”

“…The female C57BL/6 mice (The Jackson Laboratory, Bar Harbor, ME) treated with C. rodentium (American Type Culture Collection, Manassas, VA) and their pair-fed controls were the same mice described previously (Chaluvadi et al, 2008a). Infection was achieved by allowing the mice to drink a 20% sucrose solution containing C. rodentium for 24 h at a nominal bacterial concentration calculated to result in an average dose of 7 ϫ 10 8 cells/mouse.…”