Biosynthesis of leukotoxin, 9, 10-epoxy-12 octadecenoate, by leukocytes in lung lavages of rat after exposure to hyperoxia

doi:10.1016/0006-291X(86)90360-8

Biochemical and Biophysical Research Communications

Volume 134, Issue 3, 13 February 1986, Pages 1071-1078

https://doi.org/10.1016/0006-291X(86)90360-8 Get rights and content

Abstract

In lung lavages of rat after pure oxygen breathing, a toxic linoleate peroxide, 9, 10-epoxy-12-octadecenoate, and its isomer, 12,13-epoxy-9-octadecenoate were detected by HPLC analyses. The epoxide(s) was demonstrated to be biosynthesized by incubating lingleate with leukocytes collected from lung lavages, thus nominated to be leukotoxin. The chemical structures of leukotoxin and its isomer were determined by gas-chromatography/mass spectrometry and nuclear magnetic resonance measurements. Leukotoxin showed a potent uncoupling activity to rat liver mitochondrial respiration and a dose-dependent relaxation of rat stomach smooth muscle. These findings were discussed with ‘oxygen toxicity’ on the lung.

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This combination of LA- and AA-derived lipid mediators may come from neutrophil (12,13-EpOME [isoleukotoxin],38 9,10-DiHOME [leukotoxin diol],39 and 13-HODE40) and platelet (TxB2 and 12-HETE41) sources. 12,13-EpHOME, generated by CYP450 from LA during oxidative burst, uncouples mitochondrial respiration42 and is present in the lavage fluid of acute respiratory distress syndrome.43 9,10-diHOME is generated from 9(10)-EpOME (leukotoxin) by soluble epoxide hydrolase in neutrophils.39
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Citation Excerpt :
Rodent skin samples from experimentally burned animals were extracted, and a single lipid was isolated [88] that was eventually identified as 9,10-EpOME by gas chromatography/mass spectrometry and nuclear magnetic resonance analysis [102]. This metabolite was named “leukotoxin” since it was presumed that these metabolites were produced in the leukocytes [31,32,71]. The same metabolites were found to be produced by neutrophils in the lung after hyperoxic exposure [71].
Linoleic acid (LA) is the most abundant polyunsaturated fatty acid found in the Western diet. Cytochrome P450-derived LA metabolites 9,10-epoxyoctadecenoic acid (9,10-EpOME), 12,13-epoxyoctadecenoic acid (12,13-EpOME), 9,10-dihydroxy-12Z-octadecenoic acid (9,10-DiHOME) and 12,13-dihydroxy-9Z-octadecenoic acid (12,13-DiHOME) have been studied for their association with various disease states and biological functions. Previous studies of the EpOMEs and DiHOMEs have focused on their roles in cytotoxic processes, primarily in the inhibition of the neutrophil respiratory burst. More recent research has suggested the DiHOMEs may be important lipid mediators in pain perception, altered immune response and brown adipose tissue activation by cold and exercise. The purpose of this review is to summarize the current understanding of the physiological and pathophysiological roles and modes of action of the EpOMEs and DiHOMEs in health and disease.
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Cytochrome P450 (CYP) epoxygenases are a special subset of heme-containing CYP enzymes capable of performing the epoxidation of polyunsaturated fatty acids (PUFA) and the metabolism of xenobiotics. This dual functionality positions epoxygenases along a metabolic crossroad. Therefore, structure-function studies are critical for understanding their role in bioactive oxy-lipid synthesis, drug-PUFA interactions, and for designing therapeutics that directly target the epoxygenases. To better exploit CYP epoxygenases as therapeutic targets, there is a need for improved understanding of epoxygenase structure-function. Of the characterized epoxygenases, human CYP2J2 stands out as a potential target because of its role in cardiovascular physiology. In this review, the early research on the discovery and activity of epoxygenases is contextualized to more recent advances in CYP epoxygenase enzymology with respect to PUFA and drug metabolism. Additionally, this review employs CYP2J2 epoxygenase as a model system to highlight both the seminal works and recent advances in epoxygenase enzymology. Herein we cover CYP2J2’s interactions with PUFAs and xenobiotics, its tissue-specific physiological roles in diseased states, and its structural features that enable epoxygenase function. Additionally, the enumeration of research on CYP2J2 identifies the future needs for the molecular characterization of CYP2J2 to enable a new axis of therapeutic design.
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Oxylipins are lipid mediators produced from polyunsaturated fatty acid (PUFA) metabolism, and are thought to be a molecular explanation for the diverse biological effects of PUFAs. Like PUFAs, oxylipins are distinguished by their omega-6 (n6) or omega-3 (n3) chemistry. We review the use of n6 oxylipins as biomarkers of disease and their use in diagnosis and risk assessment. We show cases where oxylipins derived from linoleate (LA) or arachidonate (AA) produced by the activities of lipoxygenase, cyclooxygenase, epoxygenase, ω/ω-1 hydroxylase, and autooxidation are useful as biomarkers or risk markers. HODEs, KODEs, EpOMEs, DiHOMEs, and other metabolites of LA as well as prostanoids, HETEs, KETEs, EpETrEs, and DiHETrEs, and other metabolites of AA were useful for understanding the different signaling environments in conditions from traumatic brain injury, to major coronary events, dyslipidemia, sepsis, and more. We next evaluate interventions that alter the concentrations of n6 oxylipins in plasma. We note the utility and response of each plasma fraction, and the generally increasing utility from the non-esterified, to the esterified, to the lipoprotein fractions. Finally, we review the effects which are specifically related to n6 oxylipins and most likely to be beneficial. Both n6 and n3 oxylipins work together in an exceedingly complex matrix to produce physiological effects. This overview should provide future investigators with important perspectives for the emerging utility of n6 oxylipins as products of n6 PUFAs in human health.
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Citation Excerpt :
Together, these results support a potential role of EpOMEs in the pathology of obesity. EpOMEs have been shown to have a large array of detrimental effects on health, and are termed as “leukotoxins” since leukocytes have been shown to be a major cell type to produce EpOMEs [31–34]. Previous studies have shown that EpOMEs have an array of detrimental effects on health, inducing chemotaxis, inflammation, cardiovascular disease and pulmonary diseases [17–26].
Obesity is a serious health problem in the US and is associated with increased risks of various human diseases. To date, the mechanisms by which obesity increases the risks of a wide range of human diseases are not well understood. Here we used a LC–MS/MS-based lipidomics, which can analyze >100 bioactive lipid mediators produced by cyclooxygenase, lipoxygenase, and cytochrome P450 enzymes, to analyze plasma profiles of lipid mediators in high-fat diet induced obesity in C57BL/6 mice. Our results show that the plasma concentrations of epoxyoctadecenoic acids (EpOMEs, also termed as leukotoxins) are significantly increased in plasma of high-fat diet-fed mice, in addition, EpOMEs are among the most abundant lipid mediators detected in mouse plasma. Since substantial studies have shown that EpOMEs and their metabolites have a large array of detrimental effects on health, enhanced levels of EpOMEs could contribute to the pathology of obesity.

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Biosynthesis of leukotoxin, 9, 10-epoxy-12 octadecenoate, by leukocytes in lung lavages of rat after exposure to hyperoxia

Abstract

Arch. Intern. Med

Am. J. Physiol

Lipids