Abstract
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-α 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-α. The LPS-evoked loss in hepatic cytochrome P450 could not be prevented by blocking β-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 β-receptor-mediated sympathetic nerve pathway.
Footnotes
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Send reprint requests to: Dr. Kenneth W. Renton, Department of Pharmacology, Dalhousie University, Sir Charles Tupper Medical Bldg., Halifax Nova Scotia, Canada B3H 4H7. E-mail:Ken.Renton{at}dal.ca
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↵1 This study was supported by the Medical Research Council of Canada.
- Abbreviations:
- IFN
- interferon
- IL
- interleukin
- TNF
- tumor necrosis factor
- LPS
- lipopolysaccharide
- CNS
- central nervous system
- hsp
- heat shock protein
- EROD
- ethoxyresorufin dealkylase
- PROD
- pentoxyresorufin dealkylase
- BROD
- benzyloxyresorufin dealkylase
- Received January 25, 2000.
- Accepted April 13, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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