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Cytochromes P450, Cardiovascular Homeostasis and Disease
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Chin Eng Ong, Amelia Dong, Boon Hooi Tan, Yan Pan
All eicosanoid metabolites are derived from arachidonic acid (AA), a 20-carbon, omega-6 polyunsaturated fatty acid (PUFA) released from the cell membrane phospholipids by the cytosolic enzyme phospholipase A2 (Sudhahar et al., 2010). Cell injury, shear stress, and hormones such as bradykinin, acetylcholine, angiotensin II, and adenosine are among the phospholipase activators that initiate eicosanoid synthesis. Figure 15.1 depicts three major pathways involved in eicosanoid synthesis: the cyclooxygenase (COX) pathway, which generates prostanoids; lipoxygenase (LOX) pathway, which produces leukotrienes and HETEs; and lastly, CYP pathways (CYP epoxygenase and CYP ω-hydroxylase) that generate EETs (Oni-Orisan et al., 2014; Wang and Dubois, 2012). Two CYP isoforms, CYP5A1 and CYP8A1, are involved in generation of prostanoids in the COX pathway. More popularly known as thromboxane A2 synthase (Wang and Kulmacz, 2002), CYP5A1 is involved in platelet aggregation, whereas CYP8A1, also called prostacyclin (PGI2) synthase (Ullrich and Hecker, 1990), participates in platelet disaggregation. Thus, CYP5A1 and CYP8A1 provide a Yin-Yang mechanism for regulation of blood coagulation. CYP epoxygenases are involved in production of EETs (Spector et al., 2004) through olefin epoxidation with both CYP2J and CYP2C epoxygenases generating four EET regioisomers defined by the location of the appended oxygen atom (5,6-, 8,9-, 11,12-, and 14,15-EETs). Each regioisomer consists of a mixture of S/R and R/S enantiomers. CYP2J2, CYP2C8, and CYP2C9 are constitutively and abundantly expressed in the human heart tissue (DeLozier et al., 2007). All EETs are subsequently hydrolyzed by soluble epoxide hydrolase (sEH) (Wang and Dubois, 2012) to form the less active dihydroxyeicosatrienoic acids (DHETs) with a shorter half-life, effectively terminating their biological effects. This makes sEH a target for increasing and prolonging the actions of EETs (Harris and Hammock, 2013). CYP ω-hydroxylases catalyze ω-terminal hydroxylation to form C16–C20 alcohols of AA (16-, 17-, 18-, 19-, and 20-HETEs). Among the different ω-hydroxylases available, CYP4A and CYP4F enzymes are involved in generating 20-HETE, a vasoactive and natriuretic eicosanoid important for vascular function (Fan et al., 2016).
Biochanin A prevents 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced adipocyte dysfunction in cultured 3T3-L1 cells
Published in Journal of Environmental Science and Health, Part A, 2019
Eun Mi Choi, Kwang Sik Suh, So Young Park, Sang Ouk Chin, Sang Youl Rhee, Suk Chon
PGE2 is one of the most important mediators linking lipolysis of adipocytes with migration of macrophages.[15] In the present study, 10 nM TCDD enhanced PGE2 production (Fig. 7A). However, biochanin A (10–20 μM) significantly inhibited TCDD-stimulated PGE2 production. Biosynthesis of prostanoids through the arachidonate cyclooxygenase (COX) pathway requires several enzymatic reactions involving phospholipase A2 and COX. Thus, we examined the levels of cPLA2 and COX-1 in 3T3-L1 cells. TCDD significantly increased the levels of cPLA2 and COX-1 (Fig. 7B, C). Biochanin A diminished these TCDD-induced effects. We speculate that biochanin A inhibits the action of TCDD on preadipocytes by reducing endogenous PGE2 and downregulating cPLA2 and COX-1.
Functional biomimetic nanoparticles for drug delivery and theranostic applications in cancer treatment
Published in Science and Technology of Advanced Materials, 2018
Lei Li, Junqing Wang, Hangru Kong, Yun Zeng, Gang Liu
Overexpression of phospholipase is a pathological indicator for multiple types of cancers and other diseases, such as thrombosis, congestive heart failure and inflammation. Phospholipase A2 (PLA2) has received much attention as therapeutic targets because it can reach abnormally high concentrations in the evading zone of tumors that is presumed as a part of the defense mechanism of the host [132,133]. Therefore, nanomaterials that could produce cytotoxic compounds upon degradation by PLA2 could be used as platforms for triggered drug delivery as they can circulate in the leaky cancerous tissue and release cargo via enzymatic digestion. For example, Jensen and his coworkers have developed of a novel class of liposomes composed of lipid prodrugs by using the up-regulated phospholipase A2 type IIA (sPLA2) activity of the tumor microenvironment as a trigger for the release of anticancer ether lipids (AEL) [134]. In their study, prodrug lipids (proAEL) have been designed to make prodrug liposomes, creating both a sPLA2-dependent anticancer prodrug and a drug delivery system. In an in vitro study by employing human KATO III and COLO 205 epithelial tumor cell lines with sPLA2 secreting, liposomes consisting of proAELs led to the growth inhibition of tumor cells. The effects of proAEL liposomes have also been investigated in the COLO 205 xenograft model. A statistically significant tumor growth delay (3.4 days) was observed in the mice administrated with proAEL liposomes compared with controls, exhibiting a significant therapeutic effect. Furthermore, no significant body weight loss or systemic toxicities was observed in any of the mice.