Abstract
Cytochrome P450 (CYP)-mediated metabolism of arachidonic acid regulates inflammation in hepatic and extra-hepatic tissue. CYP2C/CYP2J-derived epoxyeicosatrienoic and dihydroxyeicosatrienoic acids (EET+DHET) elicit anti-inflammatory effects, while CYP4A/CYP4F-derived 20-hydroxyeicosatetraenoic acid (20-HETE) is pro-inflammatory. Because the impact of inflammation on CYP-mediated formation of endogenous eicosanoids is unclear, we evaluated CYP mRNA levels and CYP epoxygenase (EET+DHET) and ω-hydroxylase (20-HETE) metabolic activity in liver, kidney, lung, and heart in mice 3, 6, 24, and 48 hours following 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 hours following LPS administration. Hepatic Cyp4a12a, Cyp4a12b, and Cyp4f13 mRNA levels and 20-HETE formation were also significantly lower at 24 hours, but recovered to baseline at 48 hours, resulting in a significantly higher 20-HETE:EET+DHET formation rate ratio compared to saline-treated mice. Renal CYP mRNA levels and CYP-mediated eicosanoid metabolism were similarly suppressed 24 hours after LPS treatment. Pulmonary EET+DHET formation was lower at all time points after LPS administration, while 20-HETE formation was suppressed in a time-dependent manner, with the lowest formation rate observed at 24 hours. 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 CYP 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 CYP epoxygenase and ω-hydroxylase pathways is an effective anti-inflammatory strategy.
- arachidonic acid metabolism
- cytochrome P450
- cytokines
- eicosanoids
- extrahepatic cytochrome P450
- fatty acid metabolism
- Received July 16, 2010.
- Accepted October 13, 2010.
- The American Society for Pharmacology and Experimental Therapeutics