Activation of the acute inflammatory response alters cytochrome P450 expression and eicosanoid metabolism.
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.
Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA.
Katherine N
KN
Theken
Yangmei
Y
Deng
M Alison
MA
Kannon
Tricia M
TM
Miller
Samuel M
SM
Poloyac
Craig R
CR
Lee
D000818:Animals; D016718:Arachidonic Acid / Q000097:blood; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D015777:Eicosanoids / Q000378:metabolism*; D006321:Heart / Q000187:drug effects; D007113:Immunity, Innate; D007249:Inflammation / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism
D015777:Eicosanoids; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D016718:Arachidonic Acid; D012313:RNA; D003577:Cytochrome P-450 Enzyme System