Hepatic and renal cytochrome p450 gene regulation during citrobacter rodentium infection in wild-type and toll-like receptor 4 mutant mice.

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 (\u3c4% 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)-1beta, IL-6, and tumor necrosis factor alpha (TNFalpha) mRNAs were significantly increased in infected HeOu mice, whereas only TNFalpha mRNA was significantly increased in HeJ mice. Hepatic alpha1-acid glycoprotein was induced in both groups, whereas alpha-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

CHARACTERIZATION OF CYP4A INDUCTION IN RAT LIVER BY INFLAMMATORY STIMULI: DEPENDENCE ON SEX, STRAIN, AND INFLAMMATION-EVOKED HYPOPHAGIA

This paper is available online at http://dmd.aspetjournals.org ABSTRACT: Acute treatment of rats with bacterial endotoxin or particulate irritants induces the expression of CYP4A mRNAs in rat liver and kidney. To determine whether all or part of these effects could be caused by hypophagia associated with the treatments, we pair-fed saline-injected rats to rats injected with endotoxin or the particulate irritant BaSO 4 . The effects of endotoxin on hepatic or renal CYP4A1, CYP4A2, or CYP4A3 expression 24 h after injection were clearly distinguishable in kinetics and magnitude from those of pair feeding, indicating that the effects of endotoxin are not caused by hypophagia. Conversely, BaSO 4 treatment caused a more profound hypophagia, and pair feeding to these animals produced effects similar to those of the irritant treatment, indicating that CYP4A induction by BaSO 4 is mainly caused by reduced food intake. To gain further insight into the mechanism of induction of CYP4A by these inflammatory agents, we studied the sex dependence of their effects in Fischer 344 and Sprague-Dawley rats. No significant strain differences were observed, but the induction of hepatic CYP4A mRNAs by endotoxin or BaSO 4 was either absent in females or significantly lower than in males. This sex specificity of induction of hepatic CYP4As has been reported previously for peroxisome proliferators, and thus our results are consistent with a role for the peroxisome proliferator-activated receptor-␣ in the induction of hepatic CYP4As by inflammatory agents