The Role of Methyl-Linoleic Acid Epoxide and Diol Metabolites in the Amplified Toxicity of Linoleic Acid and Polychlorinated Biphenyls to Vascular Endothelial Cells

Slim, Rabih; Hammock, Bruce D.; Toborek, Michał; Robertson, Larry W.; Newman, John W.; Morisseau, Christophe; Watkins, Bruce A.; Saraswathi, Viswanathan; Hennig, Bernhard

doi:10.1006/taap.2001.9131

Cited by 60 publications

(48 citation statements)

References 54 publications

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“…Diols of linoleate epoxides (DiHOMEs) have been implicated in inflammatory disorders, including adult respiratory distress syndrome (9), and may be endogenous regulators of vascular permeability and inflammation (10). Histopathologic evaluation of SwissWebster mouse lung after dosing with 12,13-DiHOME show massive alveolar edema and hemorrhage with interstitial edema in vessel walls of the lung.…”

mentioning

confidence: 99%

Attenuation of tobacco smoke-induced lung inflammation by treatment with a soluble epoxide hydrolase inhibitor

Smith

Pinkerton

Watanabe

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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160

137

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Changes in the lungs due to smoking include inflammation, epithelial damage, and remodeling of the airways. Airway inflammation is likely to play a critical role in the genesis and progression of tobacco smoke-induced airway disease. Soluble epoxide hydrolase (sEH) is involved in the metabolism of endogenous chemical mediators that play an important role in inflammation. Epoxyeicosatrienoic acids (EETs) have demonstrated antiinflammatory properties, and hydrolysis of these epoxides by sEH is known to diminish this activity. To examine whether acute tobacco smokeinduced inflammation could be reduced by a sEH inhibitor, 12-(3-adamantane-1-yl-ureido)-dodecanoic acid n-butyl ester was given by daily s.c. injection to spontaneously hypertensive rats exposed to filtered air or tobacco smoke for a period of 3 days (6 h͞day). Acute exposure to tobacco smoke significantly increased by 3.2-fold (P < 0.05) the number of cells recovered by bronchoalveolar lavage. The sEH inhibitor significantly decreased total bronchoalveolar lavage cell number by 37% in tobacco smoke-exposed rats with significant reductions noted in neutrophils, alveolar macrophages, and lymphocytes. A combination of sEH inhibitor and EETs was more significant in its ability to further reduce tobacco smokeinduced inflammation compared with the sEH inhibitor alone. The sEH inhibitor led to a shift in some plasma epoxides and diols that are consistent with the hypothetical action of these compounds. We conclude that an sEH inhibitor, in the presence or absence of EETs, can attenuate, in part, inflammation associated with acute exposure to tobacco smoke. epoxyeicosatrienoic acids ͉ pulmonary ͉ antiinflammatory

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mentioning

confidence: 99%

Attenuation of tobacco smoke-induced lung inflammation by treatment with a soluble epoxide hydrolase inhibitor

Smith

Pinkerton

Watanabe

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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160

137

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“…While receiving less attention, linoleate derived dihydroxy lipids are also bioactive. These octadecanoid diols or dihydroxyoctadecenoic acids (DiHOMEs) inhibit mitochondrial respiration (8,29,30), increase vascular permeability (31), and have been identified as their glucuronide conjugates in the urine of children with generalized peroxisomal disorders (10). Therefore, the simultaneous determination of both linoleate and arachidonate derived oxidation products in urine may provide unique insights into the associations between these compounds under various physiological conditions, including disease.…”

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confidence: 99%

The simultaneous quantification of cytochrome P450 dependent linoleate and arachidonate metabolites in urine by HPLC-MS/MS

Newman

Watanabe

Hammock

2002

Journal of Lipid Research

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125

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A method for the simultaneous quantification of urinary linoleic and arachidonic acid derived epoxides and diols, as well as the arachidonate omega hydroxylated product has been developed. The method employs negative mode electrospray ionization and HPLC with tandem mass spectroscopy for quantification. Odd chain length saturated epoxy and dihydroxy fatty acids are used as analytical surrogates resulting in linear calibrations ( r 2 у 0.9995). Standard addition analyses showed that matrix effects do not prevent these surrogates from yielding reliable quantitative results. Using 4 ml urine aliquots at a final extract volume of 100 l and injecting 10 l, method detection limits and limits of quantification were р 0.5 and 1.5 nM, respectively. The sensitivity for dihydroxy lipids was from 3-to 10-fold greater than the corresponding epoxy fatty acid. Shot to shot run times of 31 min were achieved. Rodent and human urine analyses indicated the method sensitivity is sufficient for general research applications. In addition, diurnal fluctuations in linoleate and arachidonate derived metabolites were observed in human subjects.

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“…Recent studies have shown that LA and its metabolites exhibit proinflammatory effects in the vascular endothelium and cytotoxicity to proximal tubule cells, such that LA may be associated with some adverse effects as well. 29,[32][33][34] Some cell-based toxicity studies have also shown a protective effect of LA but not its diols. 35 The monoepoxides of LA, leukotoxin and isoleukotoxin, have been associated with multiorgan failure, 32 which has been linked to the production of LA diols in proximal tubule cells.…”

Section: Discussionmentioning

confidence: 99%

Salt Loading Increases Urinary Excretion of Linoleic Acid Diols and Triols in Healthy Human Subjects

et al. 2008

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Abstract-Increased dietary linoleic acid has been associated with reduced blood pressure in clinical and animal studies possibly mediated by prostaglandins. Urinary linoleate and prostaglandin metabolite excretion were investigated in subjects exposed to a salt-loading/salt-depletion regimen. Twelve healthy subjects were recruited from the New Orleans population (before Hurricaine Katrina) and admitted to the Tulane-Louisiana State University-Charity Hospital General Clinical Research Center after a 5-day outpatient lead-in phase on a 160-mmol sodium diet. On inpatient day 1, the subjects were maintained on the 160-mmol sodium diet, and a 24-hour urine specimen was collected. On day 2, the subjects received 2 L of IV normal saline over 4 hours and continued on a 160-mmol Na ϩ diet (total: 460 mmol of sodium). Two 12-hour urine collections were obtained. On day 3, the subjects received three 40-mg oral doses of furosemide, two 12-hour urine collections were obtained, and the subjects were given a 10-mmol sodium diet. Urinary oxidized lipids were measured by high-performance liquid chromatography-tandem quadrupole mass spectroscopy. The excretion of the urinary linoleate metabolites, dihydroxyoctadecamonoenoic acids, and trihydroxyoctadecamonoenoic acids increased significantly during intravenous salt loading as compared with day 1 and the salt-depleted periods. The urinary excretion of 6-keto-prostaglandin F1␣ was unaffected by salt loading but was dramatically increased 7-to 10-fold by salt depletion. Prostaglandin E2 excretion was positively correlated with sodium excretion. The saltstimulated production of linoleic acid diols and triols may inhibit tubular sodium reabsorption, thereby assisting in the excretion of the sodium load. T he dietary intake of linoleic acid (LA), an essential fatty acid, influences blood pressure. Increased dietary LA intake reduces systolic blood pressure, increases red blood cell membrane LA content, and alters red and white blood cell sodium transport processes in clinical studies. 1-7 Conversely, dietary LA deprivation in rats results in the development of salt-sensitive hypertension and an inability to excrete an acute salt load, with both effects reversed by the administration of LA. 8 -10 LA is a precursor of arachidonic acid, and it has been proposed that the effects of LA on blood pressure and salt excretion may be mediated through the production of various cytochrome P450 (CYP) eicosanoids and/or prostaglandins, including the epoxyeicosatrienoic acids (EETs) [11][12][13][14] and the prostacyclin metabolite 6-keto-prostaglandin (PG) F1␣. 15,16 Inhibition of CYP-mediated EET production has been associated with the development of hypertension in rats. 11 Dietary salt loading upregulates CYP2C23 in rats, increasing EET production and inhibiting Na ϩ reabsorption, whereas low-salt diets suppress this enzyme. 12,14 The EETs have also been shown to directly inhibit the distal tubule epithelial sodium channel. 13,14 LA, however, also serves as a substrate in various oxygenation r...

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The Role of Methyl-Linoleic Acid Epoxide and Diol Metabolites in the Amplified Toxicity of Linoleic Acid and Polychlorinated Biphenyls to Vascular Endothelial Cells

Cited by 60 publications

References 54 publications

Attenuation of tobacco smoke-induced lung inflammation by treatment with a soluble epoxide hydrolase inhibitor

Attenuation of tobacco smoke-induced lung inflammation by treatment with a soluble epoxide hydrolase inhibitor

The simultaneous quantification of cytochrome P450 dependent linoleate and arachidonate metabolites in urine by HPLC-MS/MS

Salt Loading Increases Urinary Excretion of Linoleic Acid Diols and Triols in Healthy Human Subjects

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