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Research ArticleArticle

HEPATIC AND RENAL CYTOCHROME P450 GENE REGULATION DURING CITROBACTER RODENTIUM INFECTION IN WILD-TYPE AND TOLL-LIKE RECEPTOR 4 MUTANT MICE

Terrilyn A. Richardson, Melanie Sherman, Leposava Antonovic, Sean S. Kardar, Henry W. Strobel, Daniel Kalman and Edward T. Morgan
Drug Metabolism and Disposition March 2006, 34 (3) 354-360; DOI: https://doi.org/10.1124/dmd.105.007393
Terrilyn A. Richardson
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Melanie Sherman
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Leposava Antonovic
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Sean S. Kardar
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Henry W. Strobel
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Daniel Kalman
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Edward T. Morgan
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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)-1β, IL-6, and tumor necrosis factor α (TNFα) mRNAs were significantly increased in infected HeOu mice, whereas only TNFα mRNA was significantly increased in HeJ mice. Hepatic α1-acid glycoprotein was induced in both groups, whereas α-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.

Footnotes

  • The National Institutes of Health Grants GM46897 and DK072372 (E.T.M.), NS44174 (H.W.S.), AR002157 (M.S.), and AI056067-01 (D.K.) provided funding for this study. Portions of this work were presented at the 2005 Experimental Biology Meeting, San Diego, California, April 2–6, 2005.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.105.007393.

  • ABBREVIATIONS: P450, cytochrome P450; TLR, toll-like receptor; IL, interleukin; TNFα, tumor necrosis factor α; LPS, lipopolysaccharide; PPARα, peroxisome proliferator-activated receptor α; EPEC, enteropathogenic Escherichia coli; DSS, dextran sulfate sodium; IBD, inflammatory bowel disease; RT-PCR, reverse transcription-polymerase chain reaction; GAPDH, glyceraldehyde phosphate dehydrogenase; HeOu, C3H/HeOuJ; HeJ, C3H/HeJ; Ct, threshold cycle; QPCR, quantitative PCR; RXRα, retinoid X receptor α; LP, lipoprotein.

    • Received September 15, 2005.
    • Accepted December 2, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 34 (3)
Drug Metabolism and Disposition
Vol. 34, Issue 3
1 Mar 2006
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Research ArticleArticle

HEPATIC AND RENAL CYTOCHROME P450 GENE REGULATION DURING CITROBACTER RODENTIUM INFECTION IN WILD-TYPE AND TOLL-LIKE RECEPTOR 4 MUTANT MICE

Terrilyn A. Richardson, Melanie Sherman, Leposava Antonovic, Sean S. Kardar, Henry W. Strobel, Daniel Kalman and Edward T. Morgan
Drug Metabolism and Disposition March 1, 2006, 34 (3) 354-360; DOI: https://doi.org/10.1124/dmd.105.007393

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Research ArticleArticle

HEPATIC AND RENAL CYTOCHROME P450 GENE REGULATION DURING CITROBACTER RODENTIUM INFECTION IN WILD-TYPE AND TOLL-LIKE RECEPTOR 4 MUTANT MICE

Terrilyn A. Richardson, Melanie Sherman, Leposava Antonovic, Sean S. Kardar, Henry W. Strobel, Daniel Kalman and Edward T. Morgan
Drug Metabolism and Disposition March 1, 2006, 34 (3) 354-360; DOI: https://doi.org/10.1124/dmd.105.007393
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