HEPATIC AND RENAL CYTOCHROME P450 GENE REGULATION DURINGCITROBACTER RODENTIUMINFECTION IN WILD-TYPE AND TOLL-LIKE RECEPTOR 4 MUTANT MICE

Abstract

ABSTRACT:Citrobacter rodentium is the rodent equivalent of human enteropathogenic Escherichia coli infection. This study investigated regulation of hepatic and renal cytochrome P450 (P450) mRNAs, hepatic P450 proteins, cytokines, and acute phase proteins during C. rodentium infection. Female C3H/HeOuJ (HeOu) and C3H/HeJ (HeJ) mice [which lack functional toll-like receptor 4 (TLR4)] were infected with C. rodentium by oral gavage and sacrificed 6 days later. Hepatic CYP4A10 and 4A14 mRNAs were decreased in HeOu mice (<4% of control). CYP3A11, 2C29, 4F14, and 4F15 mRNAs were reduced to 16 to 55% of control levels, whereas CYP2A5, 4F16, and 4F18 mRNAs were induced (180, 190, and 600% of control, respectively). The pattern of P450 regulation in HeJ mice was similar to that in HeOu mice for most P450s, with the exception of the TLR4 dependence of CYP4F15. Hepatic CYP2C, 3A, and 4A proteins in both groups were decreased, whereas CYP2E protein was not. Renal CYP4A10 and 4A14 mRNAs were significantly down-regulated in HeOu mice, whereas other P450s were unaffected. Most renal P450 mRNAs in infected HeJ mice were increased, notably CYP4A10, 4A14, 4F18, 2A5, and 3A13. Hepatic levels of interleukin (IL)-1␤, IL-6, and tumor necrosis factor ␣ (TNF␣) mRNAs were significantly increased in infected HeOu mice, whereas only TNF␣ mRNA was significantly increased in HeJ mice. Hepatic ␣ 1 -acid glycoprotein was induced in both groups, whereas ␣-fibrinogen and angiotensinogen were unchanged. These data indicate that hepatic inflammation induced by C. rodentium infection is mainly TLR4-independent and suggest that hepatic P450 down-regulation in this model may be cytokine-mediated.

Selective and Cytokine-Dependent Regulation of Hepatic Transporters and Bile Acid Homeostasis during Infectious Colitis in Mice

“…C. rodentium infection produces selective, mostly reversible effects on expression of cytochrome P450s (P450s) and other DMEs (Richardson and Morgan, 2005;Chaluvadi et al, 2009). Interestingly, though this Gram-negative bacterium produces LPS, the P450 gene expression changes appear to be LPS-independent, as animals lacking the LPS receptor Toll-like receptor 4 (TLR4) exhibited the same effects (Richardson et al, 2006). Just as this model of live infection exhibits distinct and specific patterns of gene expression when compared with lipopolysaccharide administration, so different disease states may present divergent impacts on gene expression through distinct mechanisms.…”

Modulation of Hepatic Cytochrome P450s byCitrobacter rodentiumInfection in Interleukin-6- and Interferon-γ-Null Mice

“…After overnight growth in Luria broth, without shaking at 37°C, the bacteria were serially diluted in sterile phosphate-buffered saline, and the nominal concentration was calculated spectrophotometrically. Infected mice were administered an estimated 2 ϫ 10 8 colony-forming units (CFU) per mouse of C. rodentium in 20% sucrose solution instead of drinking water for 24 h. This nominal dose was found to be effective in previous work (Richardson et al, 2006). To minimize differences between infections, all animals under treatment were infected with the same bacterial preparation.…”

“…Its administration to mice down-regulates the expression and/or activity of most P450s examined (Warren et al, 1999(Warren et al, , 2001Siewert et al, 2000;Li-Masters and Morgan, 2001;Ashino et al, 2004;Goralski et al, 2005;Richardson and Morgan, 2005;Xu et al, 2006;Chaluvadi et al, 2009b). We reported previously that murine hepatic P450 mRNAs are selectively modulated during Citrobacter rodentium infection in a pattern that is different from the LPS model (Richardson et al, 2006;Chaluvadi et al, 2009a). C. rodentium, a noninvasive rodent pathogen, causes colitis in mice that is similar to that caused by the human pathogen enteropathogenic Escherichia coli and is therefore used as a model of its infection (Higgins et al, 1999;Gonçalves et al, 2001).…”

EXPRESSION OF UDP-GLUCURONOSYLTRANSFERASE ISOFORM mRNAS DURING INFLAMMATION AND INFECTION IN MOUSE LIVER AND KIDNEY

“…At 16 h, livers and kidneys were collected and stored at Ϫ80°C until RNA or microsome preparation. In a second experiment, 5-week-old HeOu mice were infected with 2.0 ϫ 10 8 colony-forming units of C. rodentium in saline by gavage as described in the companion paper (Richardson et al, 2006). Control mice were administered saline by gavage the day after the infected group, and were pair-fed; i.e., they received the same amount of food eaten by the infected mice on the previous day.…”