Cytochrome P450 4A Isoform Inhibitory Profile of N-Hydroxy-N'-(4-butyl-2-methylphenyl)-formamidine (HET0016), a Selective Inhibitor of 20-HETE Synthesis

Seki, Takayuki; Miyata, Noriyuki; Laniado−Schwartzman, Michal

doi:10.1248/bpb.28.1651

Cited by 29 publications

(22 citation statements)

References 23 publications

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“…69 One of the more recently identified inhibitors is N-hydroxy-N′-(4-butyl-2-methylphenyl) formamidine (HET0016), which is the most potent inhibitor of 20-HETE synthesis in vivo and is highly specific for blocking the CYP4-catalyzed ω-hydroxylation. 70,71 Recent studies in our laboratory have shown that hydralazine can inhibit 20-HETE synthesis in renal microsomes from normotensive rats without affecting the synthesis of other CYP-derived arachidonic acid metabolites, such as epoxyeicosatrienoic acids (unpublished data).…”

Section: Pharmacologic Agents Affecting 20-hete Biosynthesis and Actionmentioning

confidence: 93%

20-HETE and Blood Pressure Regulation

Wu¹,

Gupta

García

et al. 2014

Cardiology in Review

126

148

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20-Hydroxy-5, 8, 11, 14-eicosatetraenoic acid (20-HETE) is a cytochrome P450 (CYP)–derived omega-hydroxylation metabolite of arachidonic acid. 20-HETE has been shown to play a complex role in blood pressure regulation. In the kidney tubules, 20-HETE inhibits sodium reabsorption and promotes natriuresis, thus, contributing to antihypertensive mechanisms. In contrast, in the microvasculature, 20-HETE has been shown to play a pressor role by sensitizing smooth muscle cells to constrictor stimuli and increasing myogenic tone, and by acting on the endothelium to further promote endothelial dysfunction and endothelial activation. In addition, 20-HETE induces endothelial angiotensin-converting enzyme, thus, setting forth a potential feed forward prohypertensive mechanism by stimulating the renin–angiotensin–aldosterone system. With the advancement of gene sequencing technology, numerous polymorphisms in the regulatory coding and noncoding regions of 20-HETE–producing enzymes, CYP4A11 and CYP4F2, have been associated with hypertension. This in-depth review article discusses the biosynthesis and function of 20-HETE in the cardiovascular system, the pharmacological agents that affect 20-HETE action, and polymorphisms of CYP enzymes that produce 20-HETE and are associated with systemic hypertension in humans.

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Section: Pharmacologic Agents Affecting 20-hete Biosynthesis and Actionmentioning

confidence: 93%

20-HETE and Blood Pressure Regulation

Wu¹,

Gupta

García

et al. 2014

Cardiology in Review

126

148

View full text Add to dashboard Cite

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“…20-HETE has been reported to serve as a second messenger in the mitogenic actions of a number of growth factors [3], and an important mediator of vascular endothelial growth factor (VEGF) mediated angiogenesis and vessel sprouting [4]. N-hydroxy-N-(4-butyl-2 methylphenyl)-formamidine (HET0016), a selective inhibitor of 20-HETE synthesis [5, 6], was found to inhibit the angiogenic responses to EGF, VEGF, FGF, and electrical stimulation in rats [7, 8] and block angiogenesis in the cornea stimulated by the implantation of human U251 glioblastoma cells as well as the proliferation of U251 cells in vitro [7, 9]. WIT002, an antagonist of 20-HETE, inhibited the growth of renal adenocarcinoma in nude mice [10], and the proliferation of U251 cells transfected with CYP4A1 in vitro [11].…”

Section: Introductionmentioning

confidence: 99%

Cytochrome P450 ω-hydroxylase promotes angiogenesis and metastasis by upregulation of VEGF and MMP-9 in non-small cell lung cancer

Chen

et al. 2010

Cancer Chemother Pharmacol

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Purpose Cytochrome P450 (CYP) ω-hydroxylase, mainly consisting of CYP4A and CYP4F, converts arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE) that induces angiogenic responses in vivo and in vitro. The present study examined the role of CYP ω-hydroxylase in angiogenesis and metastasis of human non-small cell lung cancer (NSCLC). Methods The effect of WIT003, a stable 20-HETE analog, on invasion was evaluated using a modified Boyden chamber in three NSCLC cell lines. A549 cells were transfected with CYP4A11 expression vector or exposed to CYP ω-hydroxylase inhibitor (HET0016) or 20-HETE antagonist (WIT002), and then ω-hydroxylation activity toward arachidonic acid and the levels of matrix metalloproteinases (MMPs) and VEGF were detected. The in vivo effects of CYP ω-hydroxylase were tested in established tumor xenografts and an experimental metastasis model in athymic mice. Results Addition of WIT003 or overexpression of CYP4A11 with an associated increase in 20-HETE production significantly induced invasion and expression of VEGF and MMP-9. Treatment of A549 cells with HET0016 or WIT002 inhibited invasion with reduction in VEGF and MMP-9. The PI3 K or ERK inhibitors also attenuated expression of VEGF and MMP-9. Compared with control, CYP4A11 transfection significantly increased tumor weight, microvessel density (MVD), and lung metastasis by 2.5-fold, 2-fold, and 3-fold, respectively. In contrast, WIT002 or HET0016 decreased tumor volume, MVD, and spontaneous pulmonary metastasis occurrences. Conclusion CYP ω-hydroxylase promotes tumor angiogenesis and metastasis by upregulation of VEGF and MMP-9 via PI3 K and ERK1/2 signaling in human NSCLC cells.

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“…These observations have led to the current hypothesis that the beneficial effect of inhibitors of the synthesis of 20-HETE on ischemia-reperfusion injury in the brain may be due to a reduction in oxidative stress and inhibition of apoptosis. To test this hypothesis, the present study examined the effects of a selective inhibitor of the synthesis of 20-HETE, N-hydroxy-N-(4-butyl-2-methylphenyl)formamidine (HET0016) (21,33), a chemically dissimilar 20-HETE antagonist, 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (6,, and a 20-HETE mimetic, 20-hydroxyeicosa-5(Z),14(Z)-dienoic acid (5,14-20-HEDE) (42), on the responses of organotypic hippocampal slices to oxygen-glucose deprivation (OGD) followed by reoxygenation in vitro. This is a well-established model of cerebral ischemic injury that exhibits a rapid decline in ATP levels, increased release of glutamate, a rise in intracellular Ca 2ϩ concentration, and the generation of ROS, mitochondrial dysfunction, and cell death by both necrotic and apoptotic pathways (4,7,25,36,40).…”

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confidence: 99%

Protective effect of 20-HETE inhibition in a model of oxygen-glucose deprivation in hippocampal slice cultures

Renić¹,

Kumar²,

Gebremedhin³

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Recent studies have indicated that inhibitors of the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE) may have direct neuroprotective actions since they reduce infarct volume after ischemia reperfusion in the brain without altering blood flow. To explore this possibility, the present study used organotypic hippocampal slice cultures subjected to oxygen-glucose deprivation (OGD) and reoxygenation to examine whether 20-HETE is released by organotypic hippocampal slices after OGD and whether it contributes to neuronal death through the generation of ROS and activation of caspase-3. The production of 20-HETE increased twofold after OGD and reoxygenation. Blockade of the synthesis of 20-HETE with N-hydroxy-N=-(4-butyl-2-methylphenol)formamidine (HET0016) or its actions with a 20-HETE antagonist, 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid, reduced cell death, as measured by the release of lactate dehydrogenase and propidium iodide uptake. Administration of a 20-HETE mimetic, 20-hydroxyeicosa-5(Z),14(Z)-dienoic acid (5,14-20-HEDE), had the opposite effect and increased injury after OGD. The death of neurons after OGD was associated with an increase in the production of ROS and activation of caspase-3. These effects were attenuated by HET0016 and potentiated after the administration of 5,14-20-HEDE. These findings indicate that the production of 20-HETE by hippocampal slices is increased after OGD and that inhibitors of the synthesis or actions of 20-HETE protect neurons from ischemic cell death. The protective effect of 20-HETE inhibitors is associated with a decrease in superoxide production and activation of caspase-3. 20-hydroxyeicosatetraenoic acid; brain; ischemic injury; superoxide; caspase-3 20-HYDROXYEICOSATETRAENOIC ACID (20-HETE) is a potent vasoconstrictor that is produced from -hydroxylation of arachidonic acid (AA) by cytochrome P-450 (CYP) enzymes in cerebral arteries (8,12). It is also produced by brain tissue (39). Plasma levels of 20-HETE increase after transient cerebral ischemia (26), and inhibitors of the synthesis and/or action of 20-HETE markedly reduce infarct size after cerebral ischemia (26,28,31,39). The mechanism of the neuroprotective effects of inhibitors of the synthesis and/or actions of 20-HETE remains unknown. They were initially assumed to improve cerebral perfusion. However, recent studies (28, 31) have demonstrated that inhibitors of the synthesis of 20-HETE have no effect on regional cerebral blood flow during the ischemic period and only attenuate the delayed postischemic fall in cerebral blood flow. Moreover, the previous finding that inhibitors of the synthesis of 20-HETE can reduce infarct size in the brain even when administered 4 h after reperfusion (26) suggests that these drugs may enhance the survival of neurons after ischemic injury independent of their effects on cerebral blood flow.In this regard, there is increasing evidence that 20-HETE stimulates oxidative stress through several mechanisms, including the activation of NADPH oxidase, phosphorylation and uncoupling ...

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Cytochrome P450 4A Isoform Inhibitory Profile of N-Hydroxy-N'-(4-butyl-2-methylphenyl)-formamidine (HET0016), a Selective Inhibitor of 20-HETE Synthesis

Cited by 29 publications

References 23 publications

20-HETE and Blood Pressure Regulation

20-HETE and Blood Pressure Regulation

Cytochrome P450 ω-hydroxylase promotes angiogenesis and metastasis by upregulation of VEGF and MMP-9 in non-small cell lung cancer

Protective effect of 20-HETE inhibition in a model of oxygen-glucose deprivation in hippocampal slice cultures

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