期刊
DRUG METABOLISM AND DISPOSITION
卷 39, 期 1, 页码 22-29出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/dmd.110.035287
关键词
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资金
- National Institutes of Health National Institute of Neurological Disorders and Stroke [R01-NS052315]
- National Institutes of Health National Center of Research Resources [S10-RR023461]
- National Institutes of Health National Institute of General Medical Sciences [R01-GM088199]
- American Foundation for Pharmaceutical Education
- University of North Carolina at Chapel Hill
- American Heart Association
- NATIONAL CENTER FOR RESEARCH RESOURCES [S10RR023461] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM088199] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS052315] Funding Source: NIH RePORTER
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 pro-inflammatory. 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 omega-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 omega-hydroxylase pathways is an effective anti-inflammatory strategy.
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