CYP-derived eicosanoids: Implications for rheumatoid arthritis.

Abstract Today the role of cytochrome P450 metabolites in inflammatory rheumatic disease, such as rheumatoid arthritis (RA) is still poorly understood. In this review we survey the current knowledge on cytochrome P450 metabolites in rheumatoid arthritis. The balance between CYP epoxygenase- and CYP ω- hydroxylase is correlated to the regulation of NF-κB. In RA patients synovial fluid there are higher levels of IL-6, which suppresses activities of CYP enzymes, such as CYP3A, CYP2C19, CYP2C9, and CYP1A2. EETs have anti-inflammatory effects, probably attributed to the PPARγ activation. EETs inhibit bone resorption and osteoclastogenesis, and can be considered as an innovative therapeutic strategy for rheumatoid arthritis. In reference to the CYP ɷ-hydroxylase pathway, 20-HETE is a pro-inflammatory mediator. While there is scarce information on the role of 20-HETE inhibitors and its antagonists in rheumatoid arthritis, the elevation of EETs levels by sEH inhibitors is a promising therapeutic strategy for rheumatoid arthritis patients. In addition, hybrid compounds, such as sEH inhibitors/FLAP inhibitors, or sEHI combined with NSAIDs/COXIBs are also important therapeutic target. However, studies investigating the effects of inflammation and rheumatic disease on CYP-mediated eicosanoid metabolism are necessary. Obtaining a better understanding of the complex role of CYP-derived eicosanoids in inflammatory rheumatic disease, such as rheumatoid arthritis will provide valuable insight for basic and clinical researchers investigation.