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Pathways of Arachidonic Acid Metabolism
Published in Murray D. Mitchell, Eicosanoids in Reproduction, 2020
Arachidonic acid liberated by these reactions can be metabolized by way of at least three major pathways (Figure 1). The most recently discovered pathway is that designated as the epoxygenase pathway.4,5 In this pathway, arachidonic acid is metabolized by way of cytochrome P450-linked monooxygenase enzymes into biologically active epoxides and thence to various vicinal diols and trihydroxy acids. This metabolic pathway was originally described in liver and kidney,4,5 but may be present in many other tissues. Information concerning this pathway, its products and the possible roles of such products in fetal and neonatal life is still limited. Hence, hereafter, attention will be focused on the other two major pathways of arachidonic acid metabolism, i.e., the cyclooxygenase and lipoxygenase pathways (Figure 1).
Cytochromes P450, Cardiovascular Homeostasis and Disease
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Chin Eng Ong, Amelia Dong, Boon Hooi Tan, Yan Pan
Recent evidence points to a different role of CYP2 isoforms in IRI of the heart. While over-expression of CYP2J2 and high EET level improve the functional recovery from IRI, CYP2C9 and CYP2C8, have been linked to poor outcome of ischemia-reperfusion (Doggrell, 2004). Both CYP2C isoforms have been demonstrated to generate reactive oxygen species (ROS), which induce deleterious effects, including mitochondrial damages and apoptosis, and accelerated ischemic damage in tissues (see Fig. 15.2). This can be explained by the fact that a CYP epoxygenase is not always just an epoxygenase because superoxide anions (), hydrogen peroxide, and hydroxyl radicals can also be generated during the CYP catalysis when electrons for the reduction of the central heme iron are transferred on to the activated bound oxygen molecule (Puntarulo and Cederbaum, 1998). ROS serve as both a cause and an effect of endothelial dysfunction. In IRI, the combination of ROS, exacerbated inflammation, and insufficient response to load results in dilatation, hypertrophy, fibrosis and scar formation following coronary occlusion, all of which result in cardiac failure. Increased ROS formation in endothelial cells was associated with overexpression of human CYP2C9, and this was completely inhibited by sulfaphenazole, the CYP2C9 specific inhibitor (Fichtlscherer et al., 2004; Fleming et al., 2001). Moreover, in an in vivo rat IRI model, intravenous administration of sulfaphenazole was found to reduce the myocardial infarct size and improve the cardiac function during the time of reperfusion (Ishihara et al., 2009). In another study, mice with selective increased endothelial expression of CYP2C8 showed larger infarct size and decreased functional recovery after ischemia-reperfusion (Edin et al., 2011). The above data indicate that type of isoform is critical for ROS generation as well as EET production in myocardial tissue. The nature and severity of IRI would therefore depend on the relative activity and expression profile of the CYP2C and CYP2J isoforms in the affected vascular and cardiac tissues.
Effects of multi-kinase inhibitors on the activity of cytochrome P450 2J2
Published in Xenobiotica, 2022
Ayaka Kojima, Masayuki Nadai, Norie Murayama, Hiroshi Yamazaki, Miki Katoh
Cytochrome P450 2J2 (CYP2J2) is an abundant epoxygenase in the heart. Its expression is also high in the lung, skeletal muscle, kidney, and gastrointestinal tissues (Bièche et al. 2007). However, its hepatic expression is low measuring only 1–2% of the total P450 (Yamazaki et al. 2006). CYP2J2 is upregulated in various cancers (Xu et al. 2013). CYP2J2 expression is markedly elevated in human carcinoma tissues in 101 of 130 patients (77%) with various types of carcinomas, relative to adjacent non-tumour tissues (Jiang et al. 2005). It can metabolise endogenous polyunsaturated fatty acids, such as arachidonic acid (AA) and linoleic acid. AA is converted into four epoxyeicosatrienoic acids (EET), namely 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET (Wu et al. 1996; Chen et al. 2011). 8,9-EET, 11,12-EET, and 14,15-EET inhibit cell apoptosis and promote carcinoma growth (Jiang et al. 2005). These also promoted the proliferation and migration of cancer cells (Atone et al. 2020; Lai and Chen 2021). Therefore, owing to its epoxygenase activity, CYP2J2 has recently attracted attention.
Omega‐3 Polyunsaturated Fatty Acids and Lung Cancer: nutrition or Pharmacology?
Published in Nutrition and Cancer, 2021
Owen M. Vega, Shaheen Abkenari, Zhen Tong, Austin Tedman, Sara Huerta-Yepez
In addition, to the COX pathway, ω-3 and ω-6 PUFAs are substrates of multiple pathways including the LOX and cytochrome P450 epoxygenases (96, 97). CYP epoxygenase produce epoxyeicosatrienoic acids (EETs) through the ω-6 PUFA, AA. These enzymes also produce epoxy docosapentaenoic acids (EDPs) through the ω-3 PUFA, DHA. AA and DHA therefore compete for CYP epoxygenase activity (98). Zhang, G et al. looked at the effects of EDPs produced from DHA, on tumor growth. They performed an experiment on C57BL/6 mice to investigate the effects of EDPs and EETs on metastasis using the LLC cell line. When EDPs and EETs were co-administered with an epoxide hydrolase inhibitor, trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), EDP inhibited tumor metastasis whereas EET increased tumor metastasis. The role of the epoxide hydrolase inhibitor elevated levels of ω-3 and ω-6 metabolites exaggerating their effects. The results of this experiment suggest that increased levels of ω-3 PUFA metabolites have a positive effect on mice by decreasing lung cancer metastasis. Conversely, the opposite effect is seen with an ω-6 diet.
Protective Effects of Dietary Capsaicin on the Initiation Step of a Two-Stage Hepatocarcinogenesis Rat Model
Published in Nutrition and Cancer, 2021
Luis Manuel Sarmiento-Machado, Guilherme Ribeiro Romualdo, Joyce Regina Zapaterini, Mariana Baptista Tablas, Ana Angélica Henrique Fernandes, Fernando Salvador Moreno, Luís Fernando Barbisan
On the other hand, 0.02% CPS-treated group (G3) showed an upregulation of Trpv1, Cyp2j4 and Grb2 genes in comparison to DEN-treated group (G1) (Table 2). Notably, our short-time (3 weeks) and low concentration (0.02%) CPS dietary intervention was able to induce Trpv1 gene expression (Table 2), suggesting an activation of this vanilloid receptor in the liver. In turn, the epoxygenase encoded by Cyp2j4 gene, which was downregulated in DEN-treated group (G1) (supplementary material, Table 3) but upregulated in 0.02% CPS-treated group (G3), is responsible for oxidizing arachidonic acid to epoxyeicosatrienoic acid (ETT) isomers that exert anti-inflammatory and cytoprotective responses (43). Finally, the Grb2 gene, downregulated in DEN group (G1) (supplementary material Table 3) and upregulated in 0.02% CPS-treated group (G3), was positively correlated to the priming phase of rat hepatocyte regeneration (44). Raw data on CPS-treated group (G3) versus DEN-treated group (G1) comparison is presented in Table 4 (supplementary material).