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Vol. 294, Issue 2, 524-530, August 2000

Hepatic and Central Nervous System Cytochrome P450 Are Down-Regulated during Lipopolysaccharide-Evoked Localized Inflammation in Brain1

Kenneth W. Renton and Tara E. Nicholson

Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada

The effect of central nervous system inflammation on the levels and activity of hepatic and brain cytochrome P450 were examined in the rat. Brain ethoxyresorufin dealkylkase (EROD) was depressed during localized inflammatory responses evoked by lipopolysaccharide (LPS) injected into the lateral ventricle. This loss was accompanied by a concomitant loss of EROD activity and cytochrome P450 in liver. Similar losses in hepatic enzyme were observed for benzyloxy-resorufin and pentoxy-resorufin dealkylase (CYP2B) and chlorzoxazone hydroxylation (CYP2E). Protein levels of CYP2D and CYP2E1 but not CYP1A also were depressed. Similar i.p. doses of LPS had no effect on hepatic cytochrome P450, indicating that the hepatic effect was not caused by LPS leakage from the central nervous system. Also in support of this contention is that heat shock protein 27 was expressed throughout the brain by LPS given i.c.v. but was undetectable in the liver. Tumor necrosis factor-alpha given i.c.v. depressed EROD activity in the brain but this was not accompanied by a concomitant loss in the liver. Hepatic EROD did respond to the i.p. injection of tumor necrosis factor-alpha . The LPS-evoked loss in hepatic cytochrome P450 could not be prevented by blocking beta -receptor-mediated sympathetic nerve activity. This study demonstrates that localized inflammatory responses in the brain cause a concomitant down-regulation of cytochrome P450 and drug-metabolizing activity in the liver and the brain. The effect on brain cytochrome P450 may be regulated via cytokine-mediated pathways but signaling to the liver does not involve a cytokine-mediated pathway nor a beta -receptor-mediated sympathetic nerve pathway.

1 This study was supported by the Medical Research Council of Canada.

0022-3565/00/2942-0524$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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