Abstract
Cytochrome P450 (P450)-mediated metabolism of arachidonic acid regulates inflammation in hepatic and extrahepatic tissue. CYP2C/CYP2J-derived epoxyeicosatrienoic and dihydroxyeicosatrienoic acids (EET+DHET) elicit anti-inflammatory effects, whereas CYP4A/CYP4F-derived 20-hydroxyeicosatetraenoic acid (20-HETE) is proinflammatory. Because the impact of inflammation on P450-mediated formation of endogenous eicosanoids is unclear, we evaluated P450 mRNA levels and P450 epoxygenase (EET+DHET) and ω-hydroxylase (20-HETE) metabolic activity in liver, kidney, lung, and heart in mice 3, 6, 24, and 48 h after intraperitoneal lipopolysaccharide (LPS) (1 mg/kg) or saline administration. Hepatic Cyp2c29, Cyp2c44, and Cyp2j5 mRNA levels and EET+DHET formation were significantly lower 24 and 48 h after LPS administration. Hepatic Cyp4a12a, Cyp4a12b, and Cyp4f13 mRNA levels and 20-HETE formation were also significantly lower at 24 h, but recovered to baseline at 48 h, resulting in a significantly higher 20-HETE/EET+DHET formation rate ratio compared with that for saline-treated mice. Renal P450 mRNA levels and P450-mediated eicosanoid metabolism were similarly suppressed 24 h after LPS treatment. Pulmonary EET+DHET formation was lower at all time points after LPS administration, whereas 20-HETE formation was suppressed in a time-dependent manner, with the lowest formation rate observed at 24 h. No differences in EET+DHET or 20-HETE formation were observed in heart. Collectively, these data demonstrate that acute activation of the innate immune response alters P450 expression and eicosanoid metabolism in mice in an isoform-, tissue-, and time-dependent manner. Further study is necessary to determine whether therapeutic restoration of the functional balance between the P450 epoxygenase and ω-hydroxylase pathways is an effective anti-inflammatory strategy.
Footnotes
- Received July 13, 2010.
- Accepted October 13, 2010.
This work was supported in part by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant R01-NS052315]; the National Institutes of Health National Center of Research Resources [Grant S10-RR023461]; the National Institutes of Health National Institute of General Medical Sciences [Grant R01-GM088199]; the American Foundation for Pharmaceutical Education (Predoctoral Fellowship); the University of North Carolina at Chapel Hill (Junior Faculty Development Award); and the American Heart Association [Beginning Grant-in-Aid].
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, or National Institutes of Health.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.035287.
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The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.ABBREVIATIONS:
- P450
- cytochrome P450
- EET
- epoxyeicosatrienoic acid
- 20-HETE
- 20-hydroxyeiocatetraenoic acid
- sEH
- soluble epoxide hydrolase
- DHET
- dihydroxyeicosatrienoic acid
- LPS
- lipopolysaccharide
- NF-κB
- nuclear factor-κB
- q
- quantitative
- RT
- reverse transcription
- PCR
- polymerase chain reaction
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- UPLC
- ultraperformance liquid chromatography
- TNF-α
- tumor necrosis factor-α.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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