Role Of Semicarbazide-sensitive Amine Oxidase Research Articles

Semicarbazide-sensitive amine oxidase activity levels in patients with acute lymphoblastic leukemia after cytotoxic chemotherapy

BackgroundThe role of Semicarbazide-sensitive amine oxidase (SSAO) in carcinogenesis is unknown; however, due to its function it may be involved in tumorigenesis via production of reactive aldehydes and hydrogen peroxide. ObjectiveThe study aimed to assess serum SSOA activity and to investigate the effect of cytotoxic chemotherapy on liver function in patients with acute lymphoblastic leukemia (ALL). Materials and MethodsSamples from 25 children with ALL were taken before and after finishing the induction phase of chemotherapy with (Daunorubicin, Vincristine VRC, L-asparaginase, Cyclophosphamide, Cytosar, Dexon, and Adriamycin). Activity of SSAO and liver function tests (alanine transferase (ALT), aspartate transferase (AST), alkaline phosphatase (ALP) and total serum bilirubin TSB) were measured using colorimetric methods before and after treatment. ResultsSignificant lower level in SSOA activity was found in 68% of the patients (P < 0.05) after chemotherapy. Significant higher levels were found after chemotherapy in ALT, AST, ALP activities and TSB levels in 92%, 80%, 72%, and 80% of the patients respectively. ConclusionThe decrease in SSAO activities after chemotherapy could be a mechanism for preventing the formation of the pro-inflammatory byproducts of SSAO. The increase in liver function could be a response to chemotherapy metabolism in liver cells.

Semicarbazide-sensitive amine oxidase and kidney disease

With better understanding of the molecular mechanisms underpinning chronic kidney disease, the roles of inflammation and fibrosis are becoming increasingly inseparable. The progression of renal disease is characterized by pathomorphological changes that consist of early inflammatory responses followed by tubulointerstitial fibrosis, tubular atrophy, and glomerular and vascular sclerosis. Currently available therapies that reduce hypertension, proteinuria, hyperglycemia, and interruption of the renin-angiotensin-aldosterone system are at best only partially effective. Hence, there remains a need to explore agents targeting nonrenin-angiotensin-aldosterone system pathways. In this review, we discuss mechanistic aspects in the physiological and pathological role of semicarbazide-sensitive amine oxidase, a protein enzyme involved in cellular trafficking and inflammation, with respect to the kidney. We explore the evidence for the use of semicarbazide-sensitive amine oxidase inhibitors as potential agents in renal fibrosis to delay the onset and progression of chronic kidney disease.

Alteration of serum semicarbazide-sensitive amine oxidase activity in chronic renal failure

Despite recent intensive investigations, physiological and pathological role of semicarbazide-sensitive amine oxidase (SSAO) is far from clear. In this study, serum SSAO activity was determined, radiochemically, in various groups of uremic patients: haemodialysed (HD), peritoneally dialysed (PD) and those receiving conservative treatment but still not dialysed (ND), as well as in controls. Reduced enzyme activity was found in HD uremic patients before and after dialysis treatment, compared to controls (5260 +/- 862 and 6011 +/- 958 pmol/h/ml vs. 8601 +/- 283 pmol/h/ml, p < 0.01 and p < 0.05, respectively). The activity was slightly lower in PD, and normal in ND patients. In HD patients SSAO activity was also determined by an assay based on the formation of hydrogen peroxide, and was found to be elevated compared to controls (2384 +/- 323 pmol/h/ml vs. 1437 +/- 72 pmol/h/ml, p < 0.05). The elevated serum SSAO activity measured through the detection of the enzyme-generated hydrogen peroxide in HD patients might indicate its contribution to the accelerated atherosclerotic disease observed in uremia.

Decreased serum activity of semicarbazide-sensitive amine oxidase (SSAO) in patients treated with second generation antipsychotics: a link to impaired glucose metabolism?

Although the treatment of schizophrenia with many second generation antipsychotics is known to be associated with metabolic changes, such as hyperglycemia or hypercholesterolemia, the underlying mechanisms of these adverse reactions remain unclear. In light of the recent focus on the involvement of semicarbazide-sensitive amine oxidase (SSAO) in glucose metabolism, we investigated SSAO serum activity in schizophrenic patients treated with antipsychotics with the objective of determining a possible link between SSAO and impaired glucose metabolism. Blood samples were drawn from 44 schizophrenic patients (24 receiving second generation antipsychotics known to disturb glucose metabolism) on day 1 and day 5 of inpatient treatment. Forty-one healthy adults with no medical condition known to influence SSAO served as controls. Of the 44 schizophrenic patients, the 24 treated with second generation antipsychotics known to disturb glucose metabolism showed significantly lower SSAO serum activity [day 1 (mean +/- SD): 477 +/- 105 mU/L; day 5: 438 +/- 86 mU/L] than the 20 patients treated with other antipsychotics not known to influence glucose metabolism (day 1: 513 +/- 124 mU/L, p = 0.359; day 5: 542 +/- 204 mU/L, p = 0.021) only after 5 days of treatment and compared to healthy controls (526 +/- 142 mU/L, p = 0.021). No differences were observed between schizophrenic patients treated with first generation antipsychotics and the controls. We found decreased SSAO serum activity exclusively in schizophrenic patients treated with second generation antipsychotics known to disturb glucose metabolism. In terms of the role of SSAO in glucose metabolism, the observed decrease in SSAO serum activity may be linked to metabolic changes that are known to occur in schizophrenic patients being treated with many second generation antipsychotics.

Semicarbazide-sensitive amine oxidase: current status and perspectives.

Semicarbazide-sensitive amine-oxidase (SSAO) is present in various human tissues and in plasma. Oxidative deamination of short-chain aliphatic amines is catalyzed by this enzyme to afford the corresponding aldehydes, ammonia and hydrogen peroxide. Methylamine and aminoacetone have been recognized to be physiological substrates for SSAO. There are several pathological states where increased serum SSAO activity have been found, such as diabetes mellitus, congestive heart failure, multiple types of cerebral infarction, uraemia, and hepatic cirrhosis. The role of SSAO in pathophysiology of diabetes has been most extensively investigated. The elevated formation of the potentially cytotoxic products of the enzyme may contribute to the endothelial injury of blood vessels, resulting in the early development of severe atherosclerosis; it may also contribute to the pathogenesis of diabetic angiopathy. It is now suggested that SSAO inhibitors may prevent the development of atherosclerosis and diabetic complications as well. Inhibitors can be conveniently subdivided into the main groups of hydrazine derivatives, arylalkylamines, propenyl- and propargylamines, oxazolidinones, and haloalkylamines. Of them, aryl(alkyl)hydrazines, and 3-halo-2-phenylallylamines are generally very strong SSAO inhibitors. Most of these inhibitors of SSAO have been originally developed for other purposes, or they are simple chemical reagents with highly reactive structural element(s); these compounds have not been able to fulfil all criteria of high potency, selectivity, and acceptable toxicity. New potent compounds with selectivity and low toxicity are needed, which may prove useful tools for understanding the roles and function of SSAO, or they may even be valuable substances for treatment of various diseases.

Vasoactive effects of methylamine in isolated human blood vessels: role of semicarbazide-sensitive amine oxidase, formaldehyde, and hydrogen peroxide.

It is hypothesized that methylamine (MA) and semicarbazide-sensitive amine oxidase (SSAO) activity are involved in the cardiovascular complications in human diabetics. To test this, we 1) determined the acute vasoactive effects of MA (1-1,000 micromol/l) in uncontracted and norepinephrine (NE; 1 micromol/l)-precontracted human blood vessels used for coronary artery bypass grafts [left internal mammary artery (LIMA), radial artery (RA), and right saphenous vein (RSV)]; 2) tested whether MA effects in LIMA and RSV were dependent on SSAO activity using the SSAO inhibitor semicarbazide (1 mmol/l, 15 min); 3) determined the effects of MA metabolites formaldehyde and hydrogen peroxide in LIMA and RSV; 4) tested whether the MA response was nitric oxide, prostaglandin, or hyperpolarization dependent; 5) measured the LIMA and RSV cGMP levels after MA exposure; and 6) quantified SSAO activity in LIMA, RA, and RSV. In NE-precontracted vessels, MA stimulated a biphasic response in RA and RSV (rapid contraction followed by prolonged relaxation) and dominant relaxation in LIMA (mean +/- SE, %relaxation: 55.4 +/- 3.9, n = 30). The MA-induced relaxation in LIMA was repeatable, nontoxic, and age independent. Semicarbazide significantly blocked MA-induced relaxation (%inhibition: 82.5 +/- 4.8, n = 7) and SSAO activity (%inhibition: 98.1 +/- 1.3, n = 26) in LIMA. Formaldehyde (%relaxation: 37.3 +/- 18.6, n = 3) and H(2)O(2) (%relaxation: 55.6 +/- 9.0, n = 9) at 1 mmol/l relaxed NE-precontracted LIMA comparable with MA. MA-induced relaxation in LIMA was nitric oxide, prostaglandin, and possibly cGMP independent and blocked by hyperpolarization. We conclude that vascular SSAO activity may convert endogenous amines, like MA, to vasoactive metabolites.

Contribution of serum and cellular semicarbazide-sensitive amine oxidase to amine metabolism and cardiovascular toxicity.

Semicarbazide-sensitive amine oxidase (SSAO) plays a role in the in vivo and in vitro toxicity of several environmental and endogenous amines. We investigated the role of SSAO as a component of cell culture medium (through addition of fetal calf serum (FCS)) compared to intracellular SSAO in the in vitro cytotoxicity of three amines and metabolites. Smooth muscle cells and beating cardiac myocytes were grown in 96-well plates and exposed to various concentrations and combinations of FCS in medium, amines (allylamine, AA; benzylamine, BZA; and methylamine, MA), and amine metabolites (aldehydes: acrolein, benzaldehyde, and formaldehyde; hydrogen peroxide, H2O2; ammonia, NH3). Amine and amine metabolite cytotoxicity was quantified by monitoring cell viability. SSAO activity was measured in FCS, cardiovascular cells, or rat plasma by a radioenzymatic assay using [14C]BZA. Our data show that AA and its aldehyde metabolite, acrolein, were the most toxic compounds to both cell types. However, AA toxicity was FCS-dependent in both cell types, while BZA, MA, and amine metabolite (i.e., aldehydes, H2O2, and NH3) cytotoxicity showed little FCS dependence. In these experiments, medium containing 10% FCS had a calculated amine metabolic capacity that was 30- to 50-fold that of the cultured smooth muscle cellular content in a single well of a 96-well plate. Our study demonstrates that SSAO in FCS contributes to amine metabolism and cytotoxicity to rat cardiovascular cells in vitro and how critical it is to evaluate serum for its role in mechanisms of amine toxicity in vitro and in vivo.

Role of Semicarbazide-sensitive Amine Oxidase on Glucose Transport and GLUT4 Recruitment to the Cell Surface in Adipose Cells

The previous characterization of an abundant population of non-adrenergic imidazoline-I2 binding sites in adipocytes and the recent demonstration of the interplay between these binding sites and amine oxidases led us to analyze the amine oxidase activity in membranes from isolated rat adipocytes. Adipocyte membranes had substantial levels of semicarbazide-sensitive amine oxidase (SSAO). SSAO activity and immunoreactive SSAO protein were maximal in plasma membranes, and they were also detectable in intracellular membranes. Vesicle immunoisolation analysis indicated that GLUT4-containing vesicles from rat adipocytes contain substantial levels of SSAO activity and immunoreactive SSAO protein. Immunotitration of intracellular GLUT4 vesicles indicated that GLUT4 and SSAO colocalize in an endosomal compartment in rat adipocytes. SSAO activity was also found in GLUT4 vesicles from 3T3-L1 adipocytes and rat skeletal muscle. Benzylamine, a substrate of SSAO activity, caused a marked stimulation of glucose transport in isolated rat adipocytes in the presence of very low vanadate concentrations that by themselves were ineffective in exerting insulin-like effects. This synergistic effect of benzylamine and vanadate on glucose transport was totally abolished in the presence of semicarbazide, a specific inhibitor of SSAO. Subcellular membrane fractionation revealed that the combination of benzylamine and vanadate caused a recruitment of GLUT4 to the plasma membrane of adipose cells. The stimulatory effects of benzylamine and vanadate on glucose transport were blocked by catalase, suggesting that hydrogen peroxide production coupled to SSAO activity plays a crucial regulatory role. Based on these results we propose that SSAO activity might contribute through hydrogen peroxide production to the in vivo regulation of GLUT4 trafficking in adipose cells.

The role of semicarbazide-sensitive amine oxidase with a high affinity for benzylamine (Bz. SSAO) in the catabolism of histamine in the mesenteric arterial bed of the rat

In the mesenteric arterial bed of the rat the semicarbazide-sensitive amine oxidase with a high affinity for benzylamine (Bz. SSAO) (E.C. 1.4.3.6) is also able to oxidize histamine. In the perfused mesenteric arterial bed of the rat the complete inhibition of the Bz. SSAO obtained with a specific inhibitor, B24, almost completely reduces the efflux of imidazole acetic acid and increases the relaxing effect of histamine. Bz. SSAO appears to be the only enzyme present in these blood vessels able to catabolize histamine.

Some aspects of the enzymic inactivation of sympathomimetic amines.

This review seeks to discuss the possible importance of monoamine oxidase (MAO) and semicarbazide-sensitive amine oxidase (SSAO) in terminating the effects of released sympathetic transmitters and in the inactivation of endogenous or administered sympathomimetic amines with particular reference to some aspects of the cardiovascular system. Use of in vitro preparations of blood vessels and of other smooth muscles, such as vas deferens and anococcygeus, has thrown light on possible roles for these deaminating enzymes, even in the inactivation of noradrenaline, while the new reversible inhibitors of MAO-A show promise as antidepressants with a reduced risk of hypertensive crises following the ingestion of tyramine-containing food. However, the role of SSAO in the in inactivation of amines remains an enigma, even though much is now known of its biochemical nature. While the pharmacological responses to amine substrates can be potentiated by inhibition of SSAO, there is a suspicion that it is product rather than substrate that is more important.