Evaluation of Fish Models of Soluble Epoxide Hydrolase Inhibition

Newman, John W.; Denton, Debra L.; Morisseau, Christophe; Koger, Cory S.; Wheelock, Craig E.; Hinton, David E.; Hammock, Bruce D.

doi:10.2307/3434922

Cited by 16 publications

(25 citation statements)

References 26 publications

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“…8 In addition, measuring the degree of SEH inhibition directly is more difficult because AUDA reversibly and competitively inhibits the SEH enzyme. 13,21,22 In the current study, the AUDA plasma levels were variable between the WKY and SHRSP animals, and could be attributable to differences in the drinking water intake between the strains. We cannot rule out possible differences in pharmacokinetics and AUDA metabolism between the rat strains.…”

Section: Discussionmentioning

confidence: 99%

“…Because AUDA reversibly and competitively inhibits the SEH enzyme, measuring SEH activity in the tissue to determine the degree of SEH inhibition is not feasible. 13,21,22 Plasma levels of AUBA reached 4 ng/ml in the SHRSP rats and 13 ng/ml in the WKY rats after 6 weeks of SEH inhibition. In the brain, AUDA levels reached 2 mol/g in the SHRSP rats and 3 mol/g in the WKY rats.…”

Section: Brain Auda and Plasma Auda Metabolite Levelsmentioning

confidence: 99%

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Soluble Epoxide Inhibition Is Protective Against Cerebral Ischemia via Vascular and Neural Protection

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Rudic

Schreihofer

et al. 2009

The American Journal of Pathology

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Inhibition of soluble epoxide hydrolase (SEH), the enzyme responsible for degradation of vasoactive epoxides, protects against cerebral ischemia in rats. However, the molecular and biological mechanisms that confer protection in normotension and hypertension remain unclear. Here we show that 6 weeks of SEH inhibition via 2 mg/day of 12-(3-adamantan-1-ylureido) dodecanoic acid (AUDA) in spontaneously hypertensive stroke-prone (SHRSP) rats protects against cerebral ischemia induced by middle cerebral artery occlusion, reducing percent hemispheric infarct and neurodeficit score without decreasing blood pressure. This level of cerebral protection was similar to that of the angiotensin-converting enzyme inhibitor, enalapril, which significantly lowered blood pressure. SEH inhibition is also protective in normotensive WistarKyoto (WKY) rats, reducing both hemispheric infarct and neurodeficit score. In SHRSP rats, SEH inhibition reduced wall-to-lumen ratio and collagen deposition and increased cerebral microvessel density, although AUDA did not alter middle cerebral artery structure or microvessel density in WKY rats. An apoptosis mRNA expression microarray of brain tissues from AUDAtreated rats revealed that AUDA modulates gene expression of mediators involved in the regulation of apoptosis in neural tissues of both WKY and SHRSP rats. Hence, we conclude that chronic SEH inhibition protects against cerebral ischemia via vascular protection in SHRSP rats and neural protection in both the SHRSP and WKY rats, indicating that SEH inhibition has broad pharmacological potential for treating ischemic stroke. Epoxyeicosatrienoic acids (EETs), lipid metabolites produced from arachidonic acid by CYP450 enzymes, are novel mediators that antagonize the sequela of hypertension, 1 match cerebral blood flow to increased neural activity and metabolic demand, promotes angiogenesis, 2 and protect against ischemia.3,4 Because ischemic stroke occurs with loss of cerebral blood flow and is strongly associated with hypertension, modulation of epoxide degradation has potential in managing ischemic stroke. Unfortunately, pharmacological utility of exogenous EETs is impractical because the epoxides are rapidly degraded by the soluble epoxide hydrolase (SEH) into their less active diol, dihydroxyeicosatrienoic acids. 5In fact, human SEH polymorphisms are linked to the incidence of ischemic stroke, 6 and this association could be related to modifications in SEH activity, and thus epoxide catabolism. 7 An alternative strategy that has been used to increase EETs systemically is SEH inhibition. 1 We previously showed that the SEH inhibitor 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA) protects against cerebral ischemia in spontaneously hypertensive stroke-prone (SHRSP) rats, an animal model of essential hypertension.8 Interestingly, chronic AUDA treatment in SHRSP rats effectively decreased infarct size induced by middle cerebral artery occlusion (MCAO)

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Section: Discussionmentioning

confidence: 99%

Section: Brain Auda and Plasma Auda Metabolite Levelsmentioning

confidence: 99%

Soluble Epoxide Inhibition Is Protective Against Cerebral Ischemia via Vascular and Neural Protection

Simpkins

Rudic

Schreihofer

et al. 2009

The American Journal of Pathology

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101

118

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“…16 These inhibitors efficiently reduce epoxide hydrolysis in several in vitro and in vivo models. 6,16,17 However, these dialkyl inhibitors have limited solubility in water and high melting point, which likely affect their in vivo efficacy and make formulation difficult. 5, 18 Recently, we reported that compounds with a polar functional group located on the fifth/sixth atom from the carbonyl group of the urea pharmacophore are potent inhibitors, and their solubility in water is also improved without drop of the inhibition potency.…”

Section: Introductionmentioning

confidence: 99%

Optimization of Amide-Based Inhibitors of Soluble Epoxide Hydrolase with Improved Water Solubility

et al. 2005

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Soluble epoxide hydrolase (sEH) plays an important role in the metabolism of endogenous chemical mediators involved in the regulation of blood pressure and inflammation. 1,3-Disubstituted ureas with a polar group located on the fifth atom from the carbonyl group of urea function are active inhibitors of sEH both in vitro and in vivo. However, their limited solubility in water and relatively high melting point lead to difficulties in formulating the compounds and poor in vivo efficacy. To improve these physical properties, the effect of structural modification of the urea pharmacophore on the inhibition potencies, water solubilities, octanol/water partition coefficients (log P), and melting points of a series of compounds was evaluated. For murine sEH, no loss of inhibition potency was observed when the urea pharmacophore was modified to an amide function, while for human sEH 2.5-fold decreased inhibition was obtained in the amide compounds. In addition, a NH group on the right side of carbonyl group of the amide pharmacophore substituted with an adamantyl group (such as compound 14) and a methylene carbon present between the adamantyl and amide groups were essential to produce potent inhibition of sEH. The resulting amide inhibitors have 10-30-fold better solubility and lower melting point than the corresponding urea compounds. These findings will facilitate synthesis of sEH inhibitors that are easier to formulate and more bioavailable.

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“…The cytochrome P450 monooxygenase families are present and have been characterised in a number of food-producing animals, including ruminants, horses, pigs, (Nebbia et al, 2003;Ioannides, 2006), fish (Wolf and Wolfe, 2005) and birds (Blevins et al, 2012). Epoxide hydrolases, the enzymes involved in the detoxication of the epoxides via formation of diols, which are conjugated and eliminated, are present in mammals (Wisniewski et al, 1987;Marini et al, 1998), fish (Newman et al, 2001) and birds (Harris et al, 2006). All these species, except cats, which have an unusually low capacity for glucuronidation (see section 3.1), also carry out conjugation reactions with sulphate and glucuronic acid (Watkins and Klaassen, 1986;James, 1987), originating hydrosoluble derivatives that are promptly eliminated in urine.…”

Section: Absorption Distribution Metabolism and Excretion (Adme) Anmentioning

confidence: 99%

Scientific Opinion on the safety and efficacy of aliphatic and aromatic hydrocarbons (chemical group 31) when used as flavourings for all animal species

2015

EFSA Journal

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Chemical group 31 consists of aliphatic and aromatic hydrocarbons, of which 17 are currently authorised for use as flavours in food. This opinion concerns nine compounds from this group. The Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) is unable to perform an assessment of 1,4(8), 12-bisabolatriene [01.016] due to the lack of data on its purity. The Panel concludes that D-limonene [01.045] is safe for all animal species, except for male rats, at the proposed maximum dose level (25 mg/kg feed). 1-Isopropyl-4-methylbenzene [01.002] is safe for all target species, except cats, at the proposed maximum dose level (25 mg/kg feed), with a margin of safety ranging from 1-fold (no margin of safety) to 3. [01.046], the calculated safe use level is 1.5 mg/kg complete feed for cattle, salmonids and non-food-producing animals and 1 mg/kg complete feed for pigs and poultry. The absence of a margin of safety would not allow the simultaneous administration in feed and water for drinking of these substances. Overall, the FEEDAP Panel is not in the position to conclude on the use of these additives in water for drinking. No safety concern would arise for the consumer from the use of these compounds up to the highest safe levels in feeds. All compounds should be considered irritant to skin, eyes and respiratory tract and as skin sensitisers. No risk for the safety for the environment is foreseen. Since all of the compounds under assessment are used in food as flavourings, and their function in feed is essentially the same as that in food, no further demonstration of efficacy is necessary. No safety concern would arise for the consumer from the use of these compounds up to the highest safe levels in feeds.All compounds should be considered irritant to skin, eyes and respiratory tract and as skin sensitisers.No risk for the safety for the environment is foreseen.

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Evaluation of Fish Models of Soluble Epoxide Hydrolase Inhibition

Cited by 16 publications

References 26 publications

Soluble Epoxide Inhibition Is Protective Against Cerebral Ischemia via Vascular and Neural Protection

Soluble Epoxide Inhibition Is Protective Against Cerebral Ischemia via Vascular and Neural Protection

Optimization of Amide-Based Inhibitors of Soluble Epoxide Hydrolase with Improved Water Solubility

Scientific Opinion on the safety and efficacy of aliphatic and aromatic hydrocarbons (chemical group 31) when used as flavourings for all animal species

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