Background: Arachidonic acid (AA) is a polyunsaturated fatty acid, released in inflammatory disease, such as rheumatoid arthritis (RA). Cyclooxygenase (COX) and lypooxygenase (LOX) pathways have received greater attention than cytochrome P450 (CYP) pathway of AA, which also plays a significant role in RA. AA is a substrate of CYP enzymes through two different pathways: the ω-hydroxylase, and epoxygenase pathways, respectively. The epoxygenase gives rise to epoxyeicosatrienoic acids (EETs) (5,6-EET, 8,9-EET, 11,12-EET, 14,15-EET), whereas ω- hydroxylase produces hydroxyeicosatetraenoic acids (HETEs) [1].

Objectives: The aim of this study is to evaluate the role of Cytochrome P450 metabolites of arachidonic acid and their therapeutic targeting in rheumatoid arthritis.

Methods: Pubmed and Scopus databases were the main databases used to identify all the studies conformed to the eligibility criteria.

Results: CYP enzymes (CYP3A, CYP2C19, CYP2C9, CYP1A2) suppression was observed in the synovial fluid of RA patients with higher IL-6 levels. EETs inhibit bone resorption and osteoclastogenesis, have an important role in blocking inflammation by reducing TNFα, and are negatively linked with pro-inflammatory cytokines (IL-1, IL-6, IL-8)[2]. The anti-inflammatory effects of EETs are potentially attributed to peroxisome proliferator–activated receptor gamma (PPARγ) activation. EETs are also metabolized through soluble epoxide hydrolase (sEH) to dihydroxyeicsatrienoic acids (DHETs), which have a pro-inflammatory activity. On the other hand, 20-HETE deriving from CYP ω-hydroxylase pathway has pro-inflammatory effect [3]. Data have shown that the genetic variations of CYP could affect the individual susceptibility to RA [4].

Conclusion: sEH inhibitors (sEHi) can not only block the inflammation caused by EETs metabolite, but can also act on LOX and COX pathway, and can be used in chronic-phase arthritis to reduce both inflammation, and the pain. In a mouse model of RA, sEHi showed decent RA assessment score improvement [5]. Moreover, data suggest that sEHi inhibit also PGE2 production, and exert an additional anti-inflammatory effect in arthritis. Since NSAIDs can lead to gastric and cardiovascular problems, sEHi are considered a better pharmacological approach in inflammatory rheumatic disease. Despite the failure of some of sEHi to reach clinical trials, we believe that CYP-derived eicosanoids should be further studied as potential target in rheumatic disease. Dual inhibitors sEHI/5-LOX activating protein (FLAP) are also very promising compounds as they can inhibit leukotriene formation, without effecting the levels of anti-inflammatory pro-resolving mediators. In perspective we suggest that multiple ligands targeting different AA pathways or mediators should be further explored as potential targets for designing new compounds to treat RA patients.

REFERENCES:

[1]M. Hoxha, B. Zappacosta. CYP-derived eicosanoids: Implications for rheumatoid arthritis. Prostaglandins Other Lipid Mediat. 146 (2020) 106405.

[2]X. Xu, X.A. Zhang, D.W. Wang, The roles of CYP450 epoxygenases and metabolites, epoxyeicosatrienoic acids, in cardiovascular and malignant diseases, Adv. Drug Deliv. Rev. 63 (8) (2011) 597–609.

[3]D. Panigrahy, A. Kaipainen, E.R. Greene, S. Huang, Cytochrome P450-derived eicosanoids: the neglected pathway in cancer, Cancer Metastasis Rev. 29 (4) (2010) 723–735

[4]S. Puntarulo, A.I. Cederbaum, Production of reactive oxygen species by microsomes enriched in specific human cytochrome P450 enzymes, Free Radic. Biol. Med. 24 (7–8) (1998) 1324–1330

[5]J. Park, M.J. Cho, H.J. Park, Analgesic effects of soluble epoxide hydrolase inhibitor in K/BxN serum transfer arthritis mouse model, Anesth. Pain Med. 14 (2019) 76–94.

Disclosure of Interests: None declared