HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 289/3/G434    most recent 00562.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Goralski, K. B. Articles by Renton, K. W. Search for Related Content PubMed PubMed Citation Articles by Goralski, K. B. Articles by Renton, K. W.

INFLAMMATION/IMMUNITY/MEDIATORS

Toll-like receptor-4 regulation of hepatic Cyp3a11 metabolism in a mouse model of LPS-induced CNS inflammation

¹Department of Pharmacology and ²Department of Pediatrics, IWK Health Centre, Dalhousie University, Halifax, Nova Scotia, Canada

Submitted 22 December 2004 ; accepted in final form 29 April 2005

Central nervous system (CNS) infection and inflammation severely reduce the capacity of cytochrome P-450 metabolism in the liver. We developed a mouse model to examine the effects of CNS inflammation on hepatic cytochrome P-450 metabolism. FVB, C57BL/6, and C3H/HeouJ mice were given Escherichia coli LPS (2.5 µg) by intracerebroventricular (ICV) injection. The CNS inflammatory response was confirmed by the elevation of TNF- and/or IL-1 proteins in the brain. In all mouse strains, LPS produced a 60–70% loss in hepatic Cyp3a11 expression and activity compared with saline-injected controls. Adrenalectomy did not prevent the loss in Cyp3a11 expression or activity, thereby precluding the involvement of the hypothalamic-adrenal-pituitary axis. Endotoxin was detectable (1–10 ng/ml) in serum between 15 and 120 min after ICV dosing of 2.5 µg LPS. Peripheral administration of 2.5 µg LPS by intraperitoneal injection produced similar serum endotoxin levels and a similar loss (60%) in Cyp3a11 expression and activity in the liver. The loss of Cyp3a11 in response to centrally or peripherally administered LPS could not be evoked in Toll-like receptor-4 (TLR4)-mutant (C3H/HeJ) mice, indicating that TLR4 signaling pathways are directly involved in the enzyme loss. In summary, we conclude that LPS is transferred from the brain to the circulation in significant quantities in a model of CNS infection or inflammation. Subsequently, LPS that has reached the circulation stimulates a TLR4-dependent mechanism in the periphery, evoking a reduction in Cyp3a11 expression and metabolism in the liver.

lipopolysaccharide; cytochrome P-450; drug metabolism

This article has been cited by other articles:

				X. Gu, S. Ke, D. Liu, T. Sheng, P. E. Thomas, A. B. Rabson, M. A. Gallo, W. Xie, and Y. Tian Role of NF-{kappa}B in Regulation of PXR-mediated Gene Expression: A MECHANISM FOR THE SUPPRESSION OF CYTOCHROME P-450 3A4 BY PROINFLAMMATORY AGENTS J. Biol. Chem., June 30, 2006; 281(26): 17882 - 17889. [Abstract] [Full Text] [PDF]