leukotriene-b4 and 20-hydroxy-5-8-11-14-eicosatetraenoic-acid

Topics: Cytochrome P-450 Enzyme System; Cytochrome P450 Family 4; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Pharmacogenetics; Warfarin

Dexamethasone is an antiemetic that is frequently administered before or after the induction of anesthesia for prevention and treatment of perioperative nausea and vomiting. Dexamethasone has anti-inflammatory and immunosuppressive effects primarily via suppression of expression of inflammatory mediators. However, its effect on the eicosanoids and docosanoids that mediate the inflammatory response and inflammation resolution are unclear. We aimed to assess the effect of a single dose of intra-operative dexamethasone on peri‑operative eicosanoids involved in inflammation including leukotriene B. A subgroup of 80 patients from the randomised controlled PADDAG trial was enrolled into this substudy. They were allocated to receive 0, 4 or 8 mg dexamethasone administered intravenously at induction of anesthesia. Blood samples were collected before and 24 h after dexamethasone, for measurement of leukocytes, hs-CRP, LTB. Compared to the administration of placebo, neutrophil count was elevated (P<0.05) 24 h after administration of 4 and 8 mg dexamethasone. Dexamethasone (8 mg) resulted in increased levels of LTB. Antiemetic doses of dexamethasone given during surgery increased plasma LTB

Topics: Adult; Antiemetics; C-Reactive Protein; Dexamethasone; Docosahexaenoic Acids; Eicosanoids; Eicosapentaenoic Acid; Fatty Acids, Unsaturated; Female; Humans; Hydroxyeicosatetraenoic Acids; Inflammation; Leukocyte Count; Leukotriene B4; Lymphocyte Count; Male; Middle Aged; Neutrophils; Perioperative Care

The role of vitamin E in both enzymatic and free radical-dependent metabolism of polyunsaturated fatty acids (PUFAs) has been well demonstrated. This study proposed a new LC-MS/MS method to quantify the main vitamin E forms, their metabolites and main PUFA species in human blood, since, at present, there are not procedures able to simultaneously determine these two classes of compounds. After the optimization of sample treatment and reverse-phase separation conditions, tandem mass spectrometry detection was evaluated experimenting both positive and negative electrospray ionisation modes. The procedure was also preliminarily adapted to assess five arachidonic acid-derived eicosanoids that could be under the influence of vitamin E function, such as LTB4 (leukotriene B4), 20-HETE (20-hydroxyeicosatetraenoic acid) and their ω-oxidation metabolites. After the validation study, the performance characteristics were confirmed analysing a certified reference material (SRM

Topics: Adult; Arachidonic Acid; Case-Control Studies; Chromatography, Liquid; Eicosanoids; Fatty Acids, Unsaturated; Female; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Male; Middle Aged; Renal Insufficiency, Chronic; Tandem Mass Spectrometry; Vitamin E

Human UDP-glucuronosyltransferases (UGTs) are major phase II enzymes in the drug metabolism system. Despite major advances in characterization of UGT gene family members, their role in clearance and homeostasis of endogenous substrates is insufficiently understood. Endobiotic substrates including bilirubin, serotonin, eicosanoids, steroid hormones, bile acids, thyroxine and fat-soluble vitamins A and D are discussed. Species- and tissue/cell-dependent regulation of UGT expression by ligand-activated transcription factors is often involved in endobiotic homeostasis. However, roles of particular UGTs are often difficult to delineate since they function together with other enzymes and transporters. Better knowledge of endobiotic UGT substrates and consequences of their conjugation may help to understand evolutionary conserved UGT functions.

Topics: Bilirubin; Feedback, Physiological; Glucuronosyltransferase; Homeostasis; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; NF-E2-Related Factor 2; Receptors, Aryl Hydrocarbon; Serotonin; Substrate Specificity; Thyroxine; Vitamin A; Vitamin D

Circulating endothelial progenitor cells (EPCs) are recruited from the blood system to sites of ischemia and endothelial damage, where they contribute to the repair and development of blood vessels. Since numerous eicosanoids including leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs) have been shown to exert potent pro-inflammatory activities, we examined their levels in chronic diabetic patients with severe cardiac ischemia in conjunction with the level and function of EPCs.. Lipidomic analysis revealed a diabetes-specific increase (p<0.05) in inflammatory and angiogenic eicosanoids including the 5-lipoxygenase-derived LTB (4.11±1.17 vs. 0.96±0.27 ng/ml), the lipoxygenase/CYP-derived 12-HETE (117.08±35.05 vs. 24.34±10.03 ng/ml), 12-HETrE (17.56±4.43 vs. 4.15±2.07 ng/ml), and the CYP-derived 20-HETE (0.32±0.04 vs. 0.06±0.05 ng/ml) the level of which correlated with BMI (p=0.0027). In contrast, levels of the CYP-derived EETs were not significantly (p=0.36) different between these two groups. EPC levels and their colony-forming units were lower (p<0.05) with a reduced viability in diabetic patients compared with non-diabetics. EPC function (colony-forming units (CFUs) and MTT assay) also negatively correlated with the circulating levels of HgA1C.. This study demonstrates a close association between elevated levels of highly pro-inflammatory eicosonoids, diabetes and EPC dysfunction in patients with cardiac ischemia, indicating that chronic inflammation impact negatively on EPC function and angiogenic capacity in diabetes.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; AC133 Antigen; Aged; Antigens, CD; Body Mass Index; Cell Survival; Chromatography, Liquid; Diabetes Mellitus; Eicosanoids; Endothelial Cells; Female; Flow Cytometry; Glycoproteins; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Lipids; Male; Middle Aged; Myocardial Ischemia; Peptides; Stem Cells; Tandem Mass Spectrometry; Vascular Endothelial Growth Factor Receptor-2

20-Hydroxyeicosatetraenoic acid (20-HETE) plays an important role in the regulation of renal tubular and vascular function and a deficiency in the renal formation of 20-HETE has been linked to the development of hypertension. The cytochrome P450 4F2 (CYP4F2) gene encodes for the major CYP enzyme responsible for the synthesis of 20-HETE in the human kidney. We screened two human sampling panels (African and European Americans: n = 24 and 23 individuals, respectively) using PCR and DNA resequencing to identify informative SNPs in the coding region of the CYP4F2 gene. Two nonsynonymous SNPs that lead to amino acid changes at position 12 (W12G) and 433 (V433M), were identified. Both of these variants were found to be frequent in both African and European American sampling panels (9-21% minor allele frequency), and the W12G polymorphism exhibited extensive linkage disequilibrium with surrounding SNPs. To determine the functional significance of these mutations on the ability of the CYP4F2 enzyme to metabolize arachidonic acid and leukotriene B(4) (LTB(4)), recombinant baculoviruses containing four different human CYP4F2 variants (i.e., W12/V433, W12/M433, G12/V433, G12/M433) were generated and the proteins were expressed in Sf9 insect cells. The presence of the M433 allele, W12/M433, or G12/M433 decreased 20-HETE production to 56-66% of control. In contrast these variants had no effect on the omega-hydroxylation of LTB(4). These findings are the first to identify a functional variant in the human CYP4F2 gene that alters the production of 20-HETE.

Topics: Animals; Arachidonic Acid; Base Sequence; Black or African American; Blotting, Western; Cell Line; Chromatography, High Pressure Liquid; Cytochrome P-450 Enzyme System; Cytochrome P450 Family 4; Gene Expression; Gene Frequency; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Linkage Disequilibrium; Mass Spectrometry; Microsomes, Liver; Polymorphism, Single Nucleotide; Spodoptera; White People