Tissue Activity and Cellular Localization of Human Semicarbazide-sensitive Amine Oxidase

Andrés, Noemí; Lizcano, José M.; Rodrı́guez, Manuel J.; Romera, Manuel; Unzeta, Mercedes; Mahy, Nicole

doi:10.1177/002215540104900208

Cited by 66 publications

(36 citation statements)

References 34 publications

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“…Thus, following these doses, the peak plasma concentration would span a concentration range that encompasses the in vitro IC 50 for inhibition of rat lung SSAO by LJP 1586. Although mouse lung contains little SSAO activity compared with that detected in rat or human lungs (Andres et al, 2001), mouse aorta contains abundant SSAO activity. SSAO activity in mouse aorta homogenates was measured ex vivo after orally administering the same doses of LJP 1586 as used in the above experiments.…”

Section: Resultsmentioning

confidence: 83%

Anti-Inflammatory Effects of LJP 1586 [Z-3-Fluoro-2-(4-methoxybenzyl)allylamine Hydrochloride], an Amine-Based Inhibitor of Semicarbazide-Sensitive Amine Oxidase Activity

O’Rourke¹,

Wang²,

Miller³

et al. 2007

J Pharmacol Exp Ther

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Semicarbazide-sensitive amine oxidase (SSAO, amine oxidase, copper-containing 3, and vascular adhesion protein-1) is a copper-containing enzyme that catalyzes the oxidative deamination of primary amines to an aldehyde, ammonia, and hydrogen peroxide. SSAO is also involved in leukocyte migration to sites of inflammation, and the enzymatic activity of SSAO is essential to this role. Thus, inhibition of SSAO enzyme activity represents a target for the development of small molecule anti-inflammatory compounds. Here, we have characterized the novel SSAO inhibitor, Z-3-fluoro-2-(4-methoxybenzyl)allylamine hydrochloride (LJP 1586), and assessed its anti-inflammatory activity. LJP 1586 is a potent inhibitor of rodent and human SSAO activity, with IC 50 values between 4 and 43 nM. The selectivity of LJP 1586 was confirmed with a broad panel of receptors and enzymes that included the monoamine oxidases A and B. Oral administration of LJP 1586 resulted in complete inhibition of rat lung SSAO, with an ED 50 between 0.1 and 1 mg/kg, and a pharmacodynamic half-life of greater than 24 h. In a mouse model of inflammatory leukocyte trafficking oral dosing with LJP 1586 resulted in significant dose-dependent inhibition of neutrophil accumulation, with an effect comparable to that of anti-leukocyte function-associated antigen-1 antibody. In a rat model of LPS-induced lung inflammation, administration of 10 mg/kg LJP 1586 resulted in a 55% significant reduction in transmigrated cells recovered by bronchoalveolar lavage. The results demonstrate that a selective, orally active small molecule inhibitor of SSAO is an effective anti-inflammatory compound in vivo and provide further support for SSAO as a therapeutic anti-inflammatory target.Semicarbazide-sensitive amine oxidase [SSAO, AOC3, and vascular adhesion protein-1 (VAP-1)] is a copper-and topaquinone (TPQ) cofactor-containing enzyme that performs the oxidative deamination of primary amines. Endogenous substrates for SSAO include methylamine, formed from adrenaline and creatine metabolism, and aminoacetone, a product of amino acid catabolism. The active enzyme is a dimer and exists as both a type II transmembrane protein and in soluble form in plasma (for reviews see Boomsma et al

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Section: Resultsmentioning

confidence: 83%

Anti-Inflammatory Effects of LJP 1586 [Z-3-Fluoro-2-(4-methoxybenzyl)allylamine Hydrochloride], an Amine-Based Inhibitor of Semicarbazide-Sensitive Amine Oxidase Activity

O’Rourke¹,

Wang²,

Miller³

et al. 2007

J Pharmacol Exp Ther

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“…It is therefore conceivable that in addition to soluble primary amines, Lox and SSAO may act on amino acids included in matrix proteins. In addition, considering our methodological approach and the size of arterial samples, it is not possible to establish the relationship between SSAO tissue expression and activity, but this has previously investigated in the work of Jaakkola et al (1999) and Andres et al (2001). In this context, further morphological, biochemical, and molecular investigations will be required to determine this relationship and the exact nature of the SSAO substrate(s) in the blood vessels.…”

Section: Discussionmentioning

confidence: 99%

Semicarbazide-sensitive Amine Oxidase in Annulo-aortic Ectasia Disease: Relation to Elastic Lamellae-associated Proteins

Sibon

Larrieu

Hadri³

et al. 2004

J Histochem Cytochem.

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Inserm U441 (IS,DL,DD,JB,J-MDL), Pessac, France, and CNRS UMR 7079 (KEH,NM,BF) and Inserm EMI U01-07 (CL,PL), Paris, France S U M M A R Y Lysyl oxidases (Lox), which are members of the amine oxidase family, are involved in the maturation of elastic lamellae and collagen fibers. Modifications of amine oxidases in idiopathic annulo-aortic ectasia disease (IAAED) have never been investigated. Our aim was to examine the expression of several proteins that might interfere with elastic fiber organization in control ( n ϭ 10) and IAAED ( n ϭ 18) aortic tissues obtained at surgery. Expression of amine oxidases and semicarbazide-sensitive amine oxidase (SSAO), and cellular phenotypic markers were examined by immunohistopathology and confocal microscopy. The expression of these proteins was assessed in relation to clinical and histomorphological features of the arterial wall. In control aorta, SSAO staining was expressed along elastic lamellae, whereas in aneurysmal areas of IAAED, SSAO was markedly decreased, in association with severe disorganization of elastic lamellae. Smooth muscle myosin heavy chain was also decreased in IAAED compared with controls, indicating smooth muscle cell dedifferentiation. Multiple regression analysis showed that elastic lamellar thickness (ELT) was correlated positively with the SSAO:elastin ratio and negatively with the Lox:elastin ratio, and that the clinical features of IAAED (aneurysm, thoracic aorta diameter, and aortic insufficiency) were positively correlated with ELT but not with SSAO. The relationship between SSAO expression and ELT suggests that this amine oxidase may be involved in elastic fiber organization. However, in advanced IAAED, the deficit in SSAO expression could be secondary to the decrease and fragmentation of elastic fibers and/or to vascular smooth muscle cell dedifferentiation. (J Histochem

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“…SSAO/VAP-1 is found in adipocytes, smooth muscle cells, and endothelial cells, and is highly expressed in the lung, aorta, liver, and ileum (Andrés et al, 2001). Membrane-bound SSAO/VAP-1 is proteolytically cleaved by a metalloprotease to release an active, soluble form of the protein (Stolen et al, 2004), which has been shown to be a biomarker of disease progression in patients with liver and kidney fibrosis (Kurkijärvi et al, 1998(Kurkijärvi et al, , 2000(Kurkijärvi et al, , 2001Lin et al, 2008), cancer (Li et al, 2011), cardiovascular disease (Li et al, 2011;Aalto et al, 2012), and metabolic disorders (Boomsma et al, 1999;Li et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

PXS-4681A, a Potent and Selective Mechanism-Based Inhibitor of SSAO/VAP-1 with Anti-Inflammatory Effects In Vivo

Foot

Yow

Schilter

et al. 2013

J Pharmacol Exp Ther

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Semicarbazide-sensitive amine oxidase (SSAO), also known as vascular adhesion protein-1 (VAP-1), is a member of the copperdependent amine oxidase family that is associated with various forms of inflammation and fibrosis. To investigate the therapeutic potential of SSAO/VAP-1 inhibition, potent and selective inhibitors with drug-like properties are required. PXS-4681A [(Z)-4-(2-(aminomethyl)-3-fluoroallyloxy)benzenesulfonamide hydrochloride] is a mechanism-based inhibitor of enzyme function with a pharmacokinetic and pharmacodynamic profile that ensures complete, longlasting inhibition of the enzyme after a single low dose in vivo.PXS-4681A irreversibly inhibits the enzyme with an apparent K i of 37 nM and a k inact of 0.26 min 21 with no observed turnover in vitro. It is highly selective for SSAO/VAP-1 when profiled against related amine oxidases, ion channels, and seven-transmembrane domain receptors, and is superior to previously reported inhibitors. In mouse models of lung inflammation and localized inflammation, dosing of this molecule at 2 mg/kg attenuates neutrophil migration, tumor necrosis factor-a, and interleukin-6 levels. These results demonstrate the drug-like properties of PXS-4681A and its potential use in the treatment of inflammation.

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Tissue Activity and Cellular Localization of Human Semicarbazide-sensitive Amine Oxidase

Cited by 66 publications

References 34 publications

Anti-Inflammatory Effects of LJP 1586 [Z-3-Fluoro-2-(4-methoxybenzyl)allylamine Hydrochloride], an Amine-Based Inhibitor of Semicarbazide-Sensitive Amine Oxidase Activity

Anti-Inflammatory Effects of LJP 1586 [Z-3-Fluoro-2-(4-methoxybenzyl)allylamine Hydrochloride], an Amine-Based Inhibitor of Semicarbazide-Sensitive Amine Oxidase Activity

Semicarbazide-sensitive Amine Oxidase in Annulo-aortic Ectasia Disease: Relation to Elastic Lamellae-associated Proteins

PXS-4681A, a Potent and Selective Mechanism-Based Inhibitor of SSAO/VAP-1 with Anti-Inflammatory Effects In Vivo

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