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Physiological and pathological implications of semicarbazide-sensitive amine oxidase
Biochimica et Biophysica Acta 1647 (2003) 193 – 199 www.bba-direct.com
Review
Physiological and pathological implications of semicarbazide-sensitive amine oxidase Peter H. Yu *, Shannon Wright, Ellen H. Fan, Zhao-Rong Lun, Diana Gubisne-Harberle Neuropsychiatry Research Unit, Department of Psychiatry, College of Medicine, University of Saskatchewan, A114 Medical Research Building, Saskatoon, Saskatchewan, Canada S7N 5E4 Received 5 July 2002; received in revised form 12 December 2002; accepted 22 January 2003
Abstract Semicarbazide-sensitive amine oxidase (SSAO) catalyzes the deamination of primary amines. Such deamination has been shown capable of regulating glucose transport in adipose cells. It has been independently discovered that the primary structure of vascular adhesion protein-1 (VAP-1) is identical to SSAO. VAP-1 regulates leukocyte migration and is related to inflammation. Increased serum SSAO activities have been found in patients with diabetic mellitus, vascular disorders and Alzheimer’s disease. The SSAO-catalyzed deamination of endogenous substrates, that is, methylamine and aminoacetone, led to production of toxic formaldehyde and methylglyoxal, hydrogen peroxide and ammonia, respectively. These highly reactive aldehydes have been shown to initiate protein cross-linkage, exacerbate advanced glycation of proteins and cause endothelial injury. Hydrogen peroxide contributes to oxidative stress. 14C-methylamine is converted to 14C-formaldehyde, which then forms labeled long-lasting protein adduct in rodents. Chronic methylamine treatment increased the excretion of malondialdehyde and microalbuminuria, and enhanced the formation of fatty streaks in C57BL/6 mice fed with an atherogenic diet. Treatment with selective SSAO inhibitor reduces atherogenesis in KKAy diabetic mice fed with high-cholesterol diet. Aminoguanidine, which blocks advanced glycation and reduces nephropathy in animals, is in fact more potent at inhibiting SSAO than its effect on glycation. It suggests that SSAO is involved in vascular disorders under certain pathological conditions. Although SSAO has been known for several decades, its physiological and pathological implications are just beginning to be recognized. D 2003 Elsevier Science B.V. All rights reserved. Keywords: Methylamine; Formaldehyde; Methylglyoxal; SSAO; VAP-1; Diabetes
1. Introduction Semicarbazide-sensitive amine oxidase (SSAO) is a group of enzymes containing copper and quinone and sensitive to semicarbazide. The enzyme is present either as membrane or soluble forms located in the vascular system and adipocytes [1]. It has been shown that this enzyme may be involved in detoxifying xenobiotic amines [2], regulating glucose uptake [3], affecting cell adhesion, that is, leukocyte trafficking [4] and may also be linked to angiogenesis [5]. Increased serum SSAO activities were found in patients with diabetic complications, vascular disorders [6 –11] and heart disease [12,13]. Interestingly, SSAO-mediated deamination of methylamine and aminoacetone leads to production of toxic formaldehyde and methylglyoxal, respectively [14]. These toxic products may * Corresponding author. Tel.: +1-306-966-8816; fax: +1-306-9668830. E-mail address: [email protected] (P.H. Yu).
be responsible, at least in part, for protein cross-linkage, oxidative stress and cytotoxicity. This seems to be consistent with several of the existing hypotheses for vascular damage and advanced protein aggregation related to vascular disorders, such as diabetic complications, atherosclerosis, Alzheimer’s disease and aging.
2. SSAO-catalyzed oxidative deamination of endogenous substrate methylamine and aminoacetone Methylamine [15 –17] and aminoacetone [18 – 20] are readily deaminated by SSAO (EC 1.4.3.6) in vitro and in vivo. Formaldehyde and methylglyoxal, respectively, as well as hydrogen peroxide and ammonia are produced. SSAO
CH3 NH2 þ O2 þ H2 O ! HCHO þ H2 O2 þ NH3 CH3 CO CH2 NH2 þ O2 þ H2 O
1570-9639/03/$ - see front matter D 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S1570-9639(03)00101-8
!CH3 COCHO þ H2 O2 þ NH3
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A large quantity of methylamine was found in urine [21,22]. It is also present in blood [23,24] and tissues [25 – 27]. Methylamine can be derived from several metabolic reactions, such as the deamination of adrenaline [28 – 30], creatine and creatinine (via sarcosine) [31,32] and choline [33]. It can be ingested from food and drink or inhaled from cigarette smoke [34]. When rats are treated with SSAO inhibitors, their urinary excretion of methylamine is increased several fold [27,35]. Direct detection of endogenous formaldehyde or methylglyoxal (i.e. as a product of an SSAO-catalyzed reaction) is only partly useful, because these aldehydes rapidly interact with cellular constituents or are metabolized. Tracing residual radioactivity after the administration of 14C-methylamine in the presence or absence of specific SSAO inhibitors confirmed the conversion of methylamine to formaldehyde, and the irreversible interaction of formaldehyde with tissue components (primarily proteins) in vivo [36]. Aminoacetone is endogenously present and is derived from glycine or threonine [37]. We recently developed a method for the determination of aminoacetone levels in tissues and urine using an HPLC method [38]. Methylglyoxal was found to be significantly increased in the blood of diabetic patients [39] and is considered to cause advanced protein glycation and diabetic complications [40].
3. Cytotoxicity of formaldehyde, methylglyoxal and H 2O 2 Formaldehyde is an extremely reactive chemical. It interacts with monoamines or amides to form methylene bridges and produces irreversibly covalently cross-linked complexes with proteins and with single-stranded DNA [41,42]. It is extremely cytotoxic and has been considered to be potentially carcinogenic, making it a subject of major environmental concern [42,43]. Formaldehyde has been thought to be metabolized by formaldehyde dehydrogenase to formic acid and detoxified intracellularly in the presence of NAD+ and reduced glutathione (GSH) [44,45]. However, the Km with respect to free formaldehyde is rather high (0.2 –0.5 mM). It seems to be uncertain, whether or not formaldehyde is metabolized via this enzyme, because the endogenous formaldehyde concentrations are much lower [46]. The interaction between endogenous formaldehyde and proteins in vivo is probably rather prominent. It is also known that serum does not contain formaldehyde dehydrogenase [47]. Formaldehyde in blood therefore cannot be metabolized unless it is first transported into erythrocytes [48]. This is a very important point with respect to formaldehyde-induced toxicity to blood vessels (see below). Methylglyoxal is also a bioactive aldehyde. Its cytotoxicity has been previously reported [49] and it can quickly cross-link proteins [50]. Increased protein cross-linkage has been recognized to be involved in the aging process, which seems to be related to chronic vascular disorders.
H2O2 is a major reactive oxygen species, which is also generated in SSAO-catalyzed deaminations. In the presence of transition metals, H2O2 can be converted to toxic hydroxyl free radicals via the Fenton reaction (H2O2+ Fe2+!*OH + OH + Fe3 +) and has been implicated in several diseases [51]. Interestingly, free radicals can be generated from formaldehyde in the presence of hydrogen peroxide (2HCHO +H2O2 ! 2HU*CMO + 2H2O) under alkaline conditions [52]. In the presence of free amino group along with formaldehyde and H2O2, however, both excited formaldehyde and singlet oxygen are generated even under physiological pH [53]. It is intriguing that both formaldehyde and H2O2 are simultaneously formed from oxidative deamination of methylamine. It is reasonable to suggest that oxidative stress can be induced by an SSAO-mediated reaction, resulting in the oxidation of LDL and glycoxidation of proteins.
4. Pathological implications of increased SSAO-catalyzed deamination Allylamine, an industrial chemical, can cause extensive and progressive vascular and myocardial lesions in several mammalian species [54]. The vascular damage induced by allylamine exhibits features very similar to those seen in human atherosclerosis. Allylamine (CH2MCHCH2NH2) is converted by vascular SSAO to the toxic acrolein (CH2M CHCHO) in vitro and in vivo [55]. The vascular toxicity of allylamine can be completely prevented by the SSAO inhibitor semicarbazide in experimental animals [56]. Unlike allylamine, methylamine and aminoacetone are present endogenously. Because both SSAO and the amine substrates are present in circulating blood, it is conceivable that the deamination of methylamine and aminoacetone can occur in blood. The products, formaldehyde, methylglyoxal and H2O2, if not detoxified, could then become harmful to the blood vessels. Methylamine, in the presence of SSAO, is indeed toxic to human endothelial cells and forms patch-like lesions [57]. Our recent results have shown that chronic administration of methylamine alters urinary excretion of prorenin, suggesting that the kidney may be damaged [36]. Our recent observation indicates that chronic methylamine treatment increases fatty streaks in C57BL/6 mice fed with a high-cholesterol diet.
5. Increase of serum SSAO activity in different pathological conditions An increase in serum SSAO activity in diabetic patients has been found in different laboratories [6 – 9]. These observations have been further confirmed in juvenile diabetes as well as in both Type I and Type II diabetes [10], and are positively correlated with the severity of diabetic retinopathy [11]. SSAO has also been shown to be increased in
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patients with congestive heart failure [12] and patients with multiple types of cerebral infarct [13]. It has also been shown that SSAO activity is positively correlated with body mass index (BMI) [10]. Interestingly, SSAO activity was also found to be increased in the blood and kidney of diabetic rats (STZ-treated) [58] and sheep (alloxan-treated) [59]. Atherogenesis is a complex process in which the lumen of blood vessels becomes narrowed by cellular and extracellular substances to the point of obstruction. Lesions, often forming at the branch points of arterial blood vessels, progress via fatty streaks, followed by formation of fibrous plaques and finally thrombus formation with deposition of fibrin and platelets [60]. An etiologic model for atherosclerosis, that is, ‘‘response-to-injury’’, has been previously proposed [61,62]. The cause of such an abnormal healing process is unclear. The atherogenesis involves endothelial dysfunction, smooth muscle proliferation and subsequently, architectural disruption. Many hypotheses regarding the mechanism of atherogenesis have been proposed. Hypercholesterolemia, oxidative stress, LDL, LDL receptors, Apo-E, advanced glycation, growth factors, factors affecting hormones, cytokines, cell – cell interaction of monocytes, abnormal lipid metabolism, etc. are all possibly involved [63]. Although rodents are generally very resistant to atherosclerosis, some strains of mice, for example, inbred C57BL/ 6 fed with an atherogenic high-cholesterol diet, will develop atherosclerotic lesions [64,65]. C57BL/6 mice, which are known to be vulnerable to atherosclerosis, exhibit significantly higher SSAO activity [66]. These findings suggest that SSAO-mediated deamination is probably (at least in part) involved in atherogenesis and vascular disorders. KKAy mice is a strain possessing features closely resembling those of non-insulin-dependent diabetes mellitus (NIDDM). It has recently been found that both selective mechanism-based SSAO inhibitor and amino-guanidine effectively reduced the oxidative stress, as shown by reduction of malondialdehyde excretion, albuminuria and the number of atherosclerotic lesions in KKAy mice fed with high-cholesterol diet over a period of 16 weeks treatment [67]. Rabbits are well known to be vulnerable to atherosclerosis. Interestingly, rabbits, like humans, exhibit very high SSAO activity. Increased SSAO-mediated deamination could be involved in the cascade of atherogenesis related to diabetic complications or other disorders. Formaldehyde (which cross-links proteins) and H2O2 (which enhances oxidative stress) derived from methylamine deamination (e.g. due to persistent high blood SSAO levels in diabetes) or increased availability of substrates can induce chronic stress, which repeatedly damage endothelial cells. It is interesting to note that such chronic formaldehyde and oxidative stress does not necessarily cause acute endothelial damage. It may induce protein cross-linkage of long-lasting structural proteins, such as collagen. The rigidity of these proteins will be gradually and cumulatively increased until dysfunction occurs. The compartment, in
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which endogenous formaldehyde is produced, is very important. It is likely that SSAO-mediated production of formaldehyde would be hazardous, because it cannot be readily detoxified. It is also interesting to note that bound SSAO was found to be facing out of the plasma membrane of vascular smooth muscle [1], suggesting that not only circulating but also tissue-bound SSAO are capable of deaminating circulating amines. SSAO is known to be selectively located in the plasma membrane of vascular smooth muscle and endothelial cells, such as blood vessels [68 –70], retina and brain microvessels [71] and cartilage [72]. These tissues are vulnerable to diabetic complications. Interestingly, such a compartment for SSAO is consistent with other independent findings, where SSAO had been identified as a vascular adhesion protein-1 (VAP-1), which is related to leukocyte trafficking and inflammation (see Section 7). It is unclear how serum and kidney SSAO activity is increased in diabetic, cerebral infarct or atherosclerotic patients. It could be a result of compensatory up-regulation (i.e. in response to increased substrates), or may be a consequence of vascular damage due to the illness, namely, SSAO is released into the blood stream from damaged SSAO-rich tissues, such as the vascular smooth muscle cells. VAP-1, which is the same protein as SSAO, is upregulated in response to inflammation [73]. The increase in serum SSAO in diabetic patients may be a result of increased expression of SSAO. Increased deamination of methylamine and/or aminoacetone by SSAO would increase toxic aldehyde levels in blood, enhance oxidative stress and cause more vascular injury and inflammation in the blood vessels. Damage in the vascular system would cause more SSAO leakage and this would create a vicious cytotoxic cycle contributing toward angiopathy.
6. Methylamine, aminoacetone and their aldehyde metabolites Urinary excretion of methylamine in uremic patients is dramatically reduced [22]. This finding is consistent with an earlier report that blood methylamine levels in uremic patients is approximately 20-fold higher than in the control populations [24]. The methylamine clearance seems to be impaired in these patients. Furthermore, accumulation of creatinine and creatine due to renal failure may also lead to increased formation of methylamine via sarcosine. Nephropathy (i.e. microangiopathy in the renal glomeruli) is a major complication associated with diabetes, and cardiovascular disorders are a common problem for uremic patients. The ‘‘flooding’’ of methylamine in the blood, where SSAO is also present, may produce a chronic ‘‘aldehyde and oxidative’’ stress condition in favor of angiopathy. Methylglyoxal, the deaminated product of aminoacetone, is increased 2- to 4-fold in the blood and kidneys
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of diabetics [74]. Methylglyoxal was observed to form protein adducts, such as with albumin [75], and this reaction was blocked by aminoguanidine [76]. This adduct formation has been claimed to be involved in the pathogenesis of diabetes mellitus [39,50,77]. The results are also consistent with the notion that increased SSAO-catalyzed deamination could be involved in pathogenesis in these patients. Cardiovascular and cerebrovascular disorders are well known to be associated with cigarette smoking and stressrelated behaviors. Adrenaline and nicotine have been shown to cause an increase in methylamine, which would subsequently be converted to formaldehyde by SSAO and perhaps related to angiopathy [30,78].
7. SSAO is identical to VAP-1; its relevance to inflammation SSAO, a copper enzyme containing TOPA as cofactor, was discovered several decades ago. The enzyme has been cloned and its primary structure has been characterized [79,80]. Interestingly, the sequence of another protein called VAP-1 has been subsequently found to be identical to SSAO [81]. Indeed, VAP-1 has been shown to be capable of deaminating amines. Its distribution is also very similar to that of SSAO. The discovery was completely independent from SSAO research. VAP-1, which contains polysialic acid, induces cell adhesion and regulates lymphocyte trafficking [82]. VAP-1 is involved in granulocyte extravasation [83] and its level has been shown to be upregulated during inflammation [73]. It is intriguing that a single protein possesses such completely different functions. It remains to be established whether or not the two functions of this protein may act in a concerted fashion. It is perhaps interesting to note that formaldehyde, the deaminated product of methylamine, can induce inflammation
and has been used as an agent to elicit inflammation (i.e. arthritis).
8. Involvement of SSAO-mediated deamination in glucose transport in the adipocytes SSAO has been found to be involved in the regulation of GLUT-4 in isolated rat adipose cells [3] and in the 3T3 F422A cell line [84]. Benzylamine, an SSAO substrate, caused a marked stimulation of glucose uptake in adipocytes in the presence of a low concentration of vanadate [85]. This induction was blocked by SSAO inhibitor semicarbazide or catalase, suggesting that hydrogen peroxide production coupled with SSAO-mediated deamination plays a crucial regulatory role. It is interesting to note that SSAO is primarily present and able to produce hydrogen peroxide on the outer plasma membrane. SSAO has been claimed to play a regulatory role in glucose uptake in adipocytes. Interestingly, SSAO-mediated deamination also mimics other insulin-like actions such as on the signal transduction pathway [85], lipid metabolism [86] and differentiation of adipocytes [84,87,88]. Recently, it has been shown that glucose uptake in cultured differentiated vascular smooth muscle cells was also enhanced by SSAO substrates [89]. Benzylamine in combination with vanadate was capable of reducing the blood glucose levels in STZ-induced diabetic rat [90]. SSAO-mediated deamination could potentially play an important role in regulating glucose uptake and adipocytes differentiation and has significant physiological and pathological implications.
9. Hypothesis SSAO, an enzyme selectively located in vascular tissues, catalyzes the deamination of methylamine and aminoace-
Scheme 1. Hypothesis: Involvement of SSAO-mediated deamination in vascular disorders.
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tone. Formaldehyde and methylglyoxal as well as H2O2 and ammonia are produced respectively, which are all potentially cytotoxic. An increase in SSAO-mediated deamination may be related to atherosclerosis, obesity and diabetic complications. The following scheme summarizes the hypothesis (Scheme 1) . Both formaldehyde and methylglyoxal are capable of cross-linking proteins and enhancing advanced glycation. This will alter functional and structural proteins, which can initiate acute damage and cause chronic hardening of blood vessels, subsequently leading to atherosclerosis. Hydrogen peroxide increases oxidative stress and is related to atherogenesis. Increased SSAO-catalyzed deamination in the adipocytes may enhance glucose uptake and lipogenesis and is potentially involved in causing unwanted weight gain.
[10]
[11]
[12]
[13] [14]
[15]
Acknowledgements [16]
The authors thank the Canadian Institute of Health, Heart and Stroke Foundation, and Saskatchewan Health for their continuous financial support.
[17]
[18]
References [1] B.A. Callingham, A.E. Crosbie, B.A. Rous, Some aspects of the pathophysiology of semicarbazide-sensitive amine oxidase enzymes, in: P.H. Yu, K.F. Tipton, A.A. Boulton (Eds.), Current Neurochemical and Pharmacological Aspects of Biogenic Amines: Their Function, Oxidative Deamination and Inhibition, Elsevier, Amsterdam, 1995, pp. 305 – 321. [2] J. Elliott, B.A. Callingham, D.F. Sharman, The influence of amine metabolizing enzymes on the pharmacology of tyramine in the isolated perfused mesenteric arterial bed of rat, Br. J. Pharmacol. 98 (1989) 515 – 522. [3] G. Enrique-Tarancon, L. Marti, N. Morin, J.M. Lizcano, M. Unzeta, L. Sevilla, M. Camps, M. Palacin, X. Testar, C. Carpene, A. Zorzano, Role of semicarbazide-sensitive amine oxidase on glucose transport and GLUT4 recruitment to the cell surface in adipose cells, J. Biol. Chem. 273 (1998) 8025 – 8032. [4] M. Salmi, J. Hellman, S. Jalkanen, The role of two distinct endothelial molecules, vascular adhesion protein-1 and peripheral lymph node addressin, in the binding of lymphocyte subsets to human lymph nodes, J. Immunol. 160 (1998) 5629 – 5636. [5] S.D. Langford, M.B. Trent, A. Balakumaran, P.J. Boor, Developmental vasculotoxicity associated with inhibition of semicarbazide-sensitive amine oxidase, Toxicol. Appl. Pharmacol. 155 (1999) 237 – 244. [6] N. Tryding, S.E. Nilsson, G. Tufvesson, R. Berg, S. Carlstrom, B. Elmfors, J.E. Nilsson, Physiological and pathological influences on serum monoamine oxidase level, Scand. J. Clin. Lab. Invest. 23 (1969) 79 – 84. [7] S.E. Nilsson, N. Tryding, G. Tufvesson, Serum monoamine oxidase in diabetes mellitus and some other internal diseases, Acta Med. Scand. 184 (1968) 105 – 108. [8] C.T. Yuen, D. Easton, K. Misch, E.L. Rhodes, Increased activity of serum amine oxidase in granuloma annulare, necrobiosis lipoidics and diabetes, Br. J. Dermatol. 11 (1987) 643 – 649. [9] F. Boomsma, F.H.M. Derks, A.H. van den Meiracker, A. Man in’tVeld, M.A.D.H. Schalekamp, Plasma semicarbazide-sensitive
[19]
[20]
[21] [22]
[23] [24]
[25]
[26] [27]
[28]
[29]
[30]
197
amine oxidase activity is elevated in diabetes mellitus and correlates with glycosylated haemoglobin, Clin. Sci. 88 (1995) 675 – 679. H. Garpenstrand, J. Ekblom, L.B. Backlund, L. Oreland, U. Rosenqvist, Elevated plasma semicarbazide-sensitive amine oxidase (SSAO) activity in Type 2 diabetes mellitus complicated by retinopathy, Diabet. Med. 16 (1999) 514 – 521. Z. Me´sza´ros, T. Szombathy, L. Raimondi, I. Karadi, L. Romics, K. Magyar, Elevated serum semicarbazide-sensitive amine oxidase activity in non-insulin-dependent diabetes mellitus: correlation with BMI and serum triglyceride, Metab. Clin. Exp. 48 (1999) 113 – 117. F. Boomsma, D.J. van Veldhuisen, P.J. de Kam, A.J.M. in’t Veld, A. Mosterd, K.I. Lie, M.A.D.H. Schalekamp, Plasma semicarbazide-sensitive amine oxidase is elevated in patients with congestive heart failure, Cardiovasc. Res. 33 (1997) 387 – 391. F. Ishizaki, Plasma benzylamine oxidase activity in cerebrovascular disease, Eur. Neurol. 30 (1990) 104 – 107. P.H. Yu, Deamination of methylamine and angiopathy; toxicity of formaldehyde, oxidative stress and relevance to protein glycoxidation in diabetes, J. Neural Transm., Suppl. 52 (1996) 201 – 216. E. Precious, C.E. Gunn, G.A. Lyles, Deamination of methylamine by semicarbazide-sensitive amine oxidase in human umbilical artery and rat aorta, Biochem. Pharmacol. 37 (1988) 707 – 713. P.H. Yu, Oxidative deamination of aliphatic amines by rat aorta semicarbazide-sensitive amine oxidase, J. Pharm. Pharmacol. 42 (1990) 882 – 884. P.J. Boor, M.B. Trent, G.A. Lyles, M. Tao, G.A.S. Ansari, Methylamine metabolism to formaldehyde by vascular semicarbazide-sensitive amine oxidase, Toxicology 73 (1992) 251 – 258. N.P. Kalapos, T. Garzo, F. Antoni, S. Mardl, Accumulation of S-Dlactolylglutathione and transient decrease of glutathione level caused by methylglyoxal load in isolated hepatocytes, Biochim. Biophys. Acta 1135 (1992) 159 – 164. G.A. Lyles, J. Chalmers, The metabolism of aminoacetone to methylglyoxal by semicarbazide-sensitive amine oxidase in human umbilical artery, Biochem. Pharmacol. 31 (1992) 1417 – 1424. G.A. Lyles, Substrate-specificity of mammalian tissue-bound semicarbazide-sensitive amine oxidase, Prog. Brain Res. 106 (1995) 293 – 303. K. Blau, Chromatographic methods for the study of amines from biological material, Biochem. J. 80 (1961) 193 – 200. P.H. Yu, R.F. Dyck, Impairment of methylamine clearance in uremic patients and its nephropathological implications, Clin. Nephrol. 49 (1998) 299 – 302. A.M. Asatoor, D.N.S. Kerr, Amines in blood and urine in relation to liver disease, Clin. Chim. Acta 6 (1961) 149 – 156. S. Baba, Y. Watanabe, F. Gejyo, M. Arakwa, High-performance liquid chromatographic determination of serum aliphatic amines in chronic renal failure, Clin. Chim. Acta 136 (1984) 49 – 56. A.D. Smith, J.B. Jepson, Chromatography of urinary and tissue amines and amino alcohols as 2,4-dinitrophenyl derivatives prepared with 2-nitrobenzene-sulfonic acid, Anal. Biochem. 18 (1967) 36 – 45. R. Nixon, Volatile amines in mouse brain: a radioassay with picogram sensitivity, Anal. Biochem. 48 (1972) 460 – 470. G.A. Lyles, S.A. McDougall, The enhanced daily excretion of urinary methylamine in rats treated with semicarbazide or hydralazine may be related to the inhibition of semicarbazide-sensitive amine oxidase activities, J. Pharm. Pharmacol. 41 (1989) 97 – 100. R.W. Schayer, L.R. Smiley, H.E. Kaplan, The metabolism of epinephrine containing isotopic carbon, J. Biol. Chem. 198 (1952) 545 – 551. M.S. Dar, P.L. Morselli, E.R. Bowman, The enzymatic systems involved in the mammalian metabolism of methylamine, Gen. Pharmacol. 16 (1985) 557 – 560. P.H. Yu, C.T. Lai, D.M. Zuo, Formation of formaldehyde from adrenaline in vivo; a potential risk factor endothelial damage, Neurochem. Res. 22 (1997) 615 – 620.
198
P.H. Yu et al. / Biochimica et Biophysica Acta 1647 (2003) 193–199
[31] J.D. Jones, P.C. Burnett, Creatinine metabolism and toxicity, Kidney Int. 7 (1975) S294 – S298. [32] P.H. Yu, Y.L. Deng, Potential cytotoxic effect of chronic administration of creatine, a nutrition supplement to augment athletic performance, Med. Hypotheses 54 (1999) 726 – 728. [33] S.H. Zeisel, J.S. Wishnok, J.K. Blusztajn, Formation of methylamines from ingested choline and lecithin, J. Pharmacol. Exp. Ther. 225 (1983) 320 – 324. [34] US Dept Health and Human Services, Constituents of tobacco smoke, USPHS Publication No. 82-50179 (1982) 322. [35] P.H. Yu, D.M. Zuo, Aminoguanidine inhibits semicarbazide-sensitive amine oxidase activity; implication for advanced glycation and angiopathy in diabetes, Diabetologia 363 (1997) 1243 – 1250. [36] P.H. Yu, D.M. Zuo, Formaldehyde produced endogenously via deamination of methylamine; a potential risk factor for initiation of endothelial injury, Atherosclerosis 120 (1996) 189 – 197. [37] M.I. Bird, P.B. Nunn, L.A.J. Lord, Formation of glycine and aminoacetone from L-threonine by rat liver mitochondria, Biochim. Biophys. Acta 802 (1984) 229 – 236. [38] Y.L. Deng, P.H. Yu, Assessment of the deamination of aminoacetone, an endogenous substrate for semicarbazide-sensitive amine oxidase, Anal. Biochem. 270 (1999) 97 – 102. [39] P.J. Thornalley, Methylglyoxal, glyoxalases and the development of diabetic complications, Amino Acids 6 (1994) 15 – 23. [40] E.W. Westwood, A.C. McLellan, P.J. Thornalley, Receptor-mediated endocytic uptake of methylglyoxal-modified serum albumin, J. Biol. Chem. 269 (1994) 32293 – 32298. [41] H.M. Bolt, Experimental toxicology of formaldehyde, J. Cancer Res. Clin. Oncol. 13 (1987) 305 – 309. [42] H.D. Heck, M. Casanova, T.B. Starr, Formaldehyde toxicity—new understanding, Toxicology 20 (1990) 397 – 426. [43] J.E. Gibson (Ed.), Formaldehyde Toxicity, Hemisphere Publ., Washington, 1983. [44] J.R. Cooper, M.M. Kini, Editorial biochemical aspects of methanol poisoning, Biochem. Pharmacol. 11 (1962) 405 – 416. [45] S. Tsuboi, M. Kawase, A. Takaka, M. Hirmatus, Y. Wada, Y. Kawakami, M. Ikeka, S. Ohmori, Purification and characterization of formaldehyde dehydrogenase from rat liver cytosol, J. Biochem. 111 (1992) 465 – 471. [46] H.D. Heck, M. Casanova, Isotope effects and their implications for the covalent binding of inhaled [3H]-and [14C]-formaldehyde in the rat nasal mucosa, Toxicol. Appl. Pharmacol. 89 (1987) 123 – 130. [47] A. Helander, O. Tottmar, Metabolism of biogenic aldehydes in isolated human blood cells, platelets and in plasma, Biochem. Pharmacol. 36 (1987) 1077 – 1082. [48] G.N. Malorny, N. Rietbrock, M. Schneider, The oxidation of formaldehyde to formic acid in the blood and contribution to the metabolism of formaldehyde, Naunyn-Schmiedeberg’s Arch. Exp. Pathol. Pharmakol. 250 (1965) 419 – 436. [49] L.G. Egyud, A. Szent-Gyorgyi, Cancer static action of methylglyoxal, Science 160 (1968) 1140. [50] R.H. Nagaraj, I.N. Shipanova, F.M. Faust, Protein cross-linking by the Mailard reaction. Isolation, characterization and in vivo detection of a lysine – lysine cross-link derived from methylglyoxal, J. Biol. Chem. 271 (1996) 19338 – 19345. [51] H. Sies, Oxidative Stress; Oxidants and Antioxidants, Academic Press, London, 1991. [52] K. Lichszteld, L. Kruk, Singlet molecular oxygen in formaldehyde oxidation, Z. Phys. Chem. (N. F.) 108 (1977) 167 – 172. [53] L. Tre´zl, J. Pipek, Formation of exited formaldehyde in model reactions simulating real biological system, J. Mol. Struct. 170 (1988) 213 – 223. [54] P.J. Boor, R.M. Hysmith, Allylamine cardiovascular toxicity, Toxicology 44 (1987) 129 – 144. [55] T.J. Nelson, P.J. Boor, Allylamine cardiotoxicity: IV. Metabolism to acrolein by cardiovascular tissues, Biochem. Pharmacol. 31 (1982) 509 – 514.
[56] P.J. Boor, T.J. Nelson, Allylamine cardiotoxicity: III. Protection by semicarbazide and in vivo derangements of monoamine oxidase, Toxicology 18 (1980) 87 – 102. [57] P.H. Yu, D.M. Zuo, Methylamine, a potential endogenous toxin for vascular tissues: formation of formaldehyde via enzymatic deamination and the cytotoxic effects on endothelial cells, Diabetes 42 (1993) 594 – 603. [58] B.E. Hayes, D.E. Clarke, Semicarbazide-sensitive amine oxidase activity in streptozotocin diabetic rats, Res. Commun. Chem. Pathol. Pharmacol. 69 (1990) 71 – 83. [59] J. Elliott, A.L. Fowden, B.A. Callingham, D.F. Sharman, M. Silver, Physiological and pathological influences on sheep blood plasma amine oxidase: effect of pregnancy and experimental alloxan-induced diabetes mellitus, Res. Vet. Sci. 50 (1991) 334 – 339. [60] J.L. Breslow, Mouse models of atherosclerosis, Science 272 (1996) 685 – 688. [61] R. Ross, The pathogenesis of atherosclerosis—an update, N. Engl. J. Med. 314 (1986) 488 – 500. [62] R. Ross, L. Harker, Hyperlipidemia and atherosclerosis; chronic hyperlipidemia initiates and maintains lesion by endothelial cell desquamation and lipid accumulation, Science 193 (1976) 1094 – 1100. [63] M. Sanders, Molecular and cellular concepts in atherosclerosis, Pharmacol. Ther. 61 (1994) 109153. [64] B. Paigen, A. Morrow, C. Brandon, D. Mitchell, P.A. Holmes, Variation in susceptibility to atherosclerosis among inbred strains of mice, Atherosclerosis 57 (1985) 65 – 73. [65] B. Paigen, B.Y. Ishida, J. Verstuyft, R.B. Winter, D. Albee, Atherosclerosis susceptibility differences among progenitors of recombinant inbred strains of mice, Arteriosclerosis 10 (1990) 316 – 323. [66] P.H. Yu, Y.L. Deng, Endogenous formaldehyde and vulnerability of atherosclerosis: involvement of semicarbazide-sensitive amine oxidase-mediated methylamine turnover, Atherosclerosis 140 (1999) 357 – 363. [67] P.H. Yu, M. Wang, Y.L. Deng, H. Fan, L. Shira-Bock, Effect of semicarbazide-sensitive amine oxidase inhibitor on atherogenesis in KKAy diabetic mice fed with high cholesterol diet, Diabetologia 45 (2002) 1255 – 1262. [68] M. Wibo, A.T. Duong, T. Godfraind, Subcellular location of semicarbazide-sensitive amine oxidase in rat aorta, Eur. J. Biochem. 112 (1980) 87 – 94. [69] R. Lewinsohn, Amine oxidase in human blood vessels and non-vascular smooth muscle, J. Pharm. Pharmacol. 33 (1981) 569 – 575. [70] G.A. Lyles, I. Singh, Vascular smooth muscle cells: a major source of the semicarbazide-sensitive amine oxidase of the rat aorta, J. Pharm. Pharmacol. 37 (1985) 637 – 643. [71] D.M. Zuo, P.H. Yu, Semicarbazide-sensitive amine oxidase and monoamine oxidase in rat brain microvessels, meninges, retina and eye sclera, Brain Res. Bull. 33 (1994) 307 – 311. [72] G.A. Lyles, K.H. Bertie, Properties of a semicarbazide-sensitive amine oxidase in rat articular cartilage, Pharmacol. Toxicol. (Suppl.) 1 (1987) 33. [73] R. Kurkijarvi, D.H. Adams, R. Leino, T. Mottonen, S. Jalkanen, M. Salmi, Circulating form of human vascular adhesion protein-1 (VAP-1): increased serum levels in inflammatory liver diseases, J. Immunol. 161 (1998) 1549 – 1557. [74] A.C. McLellan, S.A. Phillips, P.J. Thornalley, The assay of methylglyoxal in biological systems by derivatization with diamno-4,5-dimethoxybenzene, Anal. Biochem. 206 (1992) 17 – 23. [75] T.W.C. Lo, M.E. Westwood, A.C. McLellan, T. Selwood, P.J. Thornalley, Binding and modification of proteins by methylglyoxal under physiological conditions, J. Biol. Chem. 269 (1994) 32299 – 32305. [76] T.W.C. Lo, T. Selwood, P.J. Thornalley, The reaction of methylglyoxal with aminoguanidine under physiological conditions and prevention of methylglyoxal binding to plasma proteins, Biochem. Pharmacol. 48 (1994) 1865 – 1870. [77] A.C. McLellan, P.J. Thornalley, J. Benn, P.H. Sonksen, Glyoxalase
P.H. Yu et al. / Biochimica et Biophysica Acta 1647 (2003) 193–199
[78]
[79]
[80]
[81]
[82] [83]
[84]
[85]
system in clinical diabetes mellitus and correlation with diabetic complications, Clin. Sci. Colch. 87 (1994) 21 – 29. P.H. Yu, Increase of formation of methylamine and formaldehyde in vivo after administration of nicotine and potential cytotoxicity, Neurochem. Res. 23 (1998) 1207 – 1212. N.J. Morris, A. Durett, R. Aebersold, S.A. Ross, S.R. Keller, G.E. Lienhard, Membrane amine oxidase cloning and identification as a major protein in the adipocyte plasma membrane, J. Biol. Chem. 272 (1997) 9388 – 9392. X. Zhang, W.S. McIntire, Cloning and sequencing of a copper-containing, topa quinone-containing monoamine oxidase from human placenta, Gene 179 (1996) 279 – 286. D.J. Smith, M. Salmi, P. Bono, J. Hellman, T. Leu, S. Jalkanen, Cloning of vascular adhesion protein-1; reveals a novel multifunctional adhesion molecule, J. Exp. Med. 188 (1998) 17 – 27. M. Salmi, S. Jalkanen, VAP-1: an adhesin and an enzyme, Trends Immunol. 22 (2001) 211 – 216. S. Tohka, M. Laukkanen, S. Jalkanen, M. Salmi, Vascular adhesion protein-1 (VAP-1) functions as a molecular brake during granulocyte rolling and mediates recruitment in vivo, FASEB J. 15 (2001) 373 – 382. E. Fontana, J. Boucher, L. Marti, J.M. Lizcano, X. Testar, A. Zorzano, C. Carpene, Amine oxidase substrates mimic several of the insulin effects on adipocyte differentiation in 3T3 F442A cells, Biochem. J. 356 (2001) 769 – 777. G. Enrique-Tarancon, I. Castan, N. Morin, L. Marti, A. Abella, M. Camps, R. Casamitjana, M. Palacin, X. Testar, E. Degerman, C. Car-
[86]
[87]
[88]
[89]
[90]
199
pene, A. Zorzano, Substrates of semicarbazide-sensitive amine oxidase co-operate with vanadate to stimulate tyrosine phosphorylation of insulin-receptor-substrate proteins, phosphoinositide 3-kinase activity and GLUT4 translocation in adipose cells, Biochem. J. 350 (2000) 171 – 180. N. Morin, J.M. Lizcano, E. Fontana, L. Marti, F. Smih, P. Rouet, D. Prevot, A. Zorzano, M. Unzeta, C. Carpene, Semicarbazide-sensitive amine oxidase substrates stimulate glucose transport and inhibit lipolysis in human adipocytes, J. Pharmacol. Exp. Ther. 297 (2001) 563 – 572. N. Mercier, M. Moldes, K. El-Hadri, B. Feve, Semicarbazide-sensitive amine oxidase activation promotes adipose conversion of 3T3-L1 cells, Biochem. J. 358 (2001) 335 – 342. N. Morin, J.M. Lizcano, E. Fontana, L. Marti, F. Smih, P. Rouet, D. Prevot, A. Zorzano, M. Unzeta, C. Carpene, Semicarbazide-sensitive amine oxidase substrates stimulate glucose transport and inhibit lipolysis in human adipocytes, J. Pharmacol. Exp. Ther. 297 (2001) 563 – 572. K. El-Hadri, M. Moldes, N. Mercier, M. Andreani, J. Pairault, B. Feve, Semicarbazide-sensitive amine oxidase in vascular smooth muscle cells: differentiation-dependent expression and role in glucose uptake, Arterioscler. Thromb. Vasc. Biol. 22 (2002) 89 – 94. L. Marti, A. Abella, C. Carpene, M. Palacin, X. Testar, A. Zorzano, Combined treatment with benzylamine and low dosages of vanadate enhances glucose tolerance and reduces hyperglycemia in streptozotocin-induced diabetic rats, Diabetes 50 (2001) 2061 – 2068.
Review
Physiological and pathological implications of semicarbazide-sensitive amine oxidase Peter H. Yu *, Shannon Wright, Ellen H. Fan, Zhao-Rong Lun, Diana Gubisne-Harberle Neuropsychiatry Research Unit, Department of Psychiatry, College of Medicine, University of Saskatchewan, A114 Medical Research Building, Saskatoon, Saskatchewan, Canada S7N 5E4 Received 5 July 2002; received in revised form 12 December 2002; accepted 22 January 2003
Abstract Semicarbazide-sensitive amine oxidase (SSAO) catalyzes the deamination of primary amines. Such deamination has been shown capable of regulating glucose transport in adipose cells. It has been independently discovered that the primary structure of vascular adhesion protein-1 (VAP-1) is identical to SSAO. VAP-1 regulates leukocyte migration and is related to inflammation. Increased serum SSAO activities have been found in patients with diabetic mellitus, vascular disorders and Alzheimer’s disease. The SSAO-catalyzed deamination of endogenous substrates, that is, methylamine and aminoacetone, led to production of toxic formaldehyde and methylglyoxal, hydrogen peroxide and ammonia, respectively. These highly reactive aldehydes have been shown to initiate protein cross-linkage, exacerbate advanced glycation of proteins and cause endothelial injury. Hydrogen peroxide contributes to oxidative stress. 14C-methylamine is converted to 14C-formaldehyde, which then forms labeled long-lasting protein adduct in rodents. Chronic methylamine treatment increased the excretion of malondialdehyde and microalbuminuria, and enhanced the formation of fatty streaks in C57BL/6 mice fed with an atherogenic diet. Treatment with selective SSAO inhibitor reduces atherogenesis in KKAy diabetic mice fed with high-cholesterol diet. Aminoguanidine, which blocks advanced glycation and reduces nephropathy in animals, is in fact more potent at inhibiting SSAO than its effect on glycation. It suggests that SSAO is involved in vascular disorders under certain pathological conditions. Although SSAO has been known for several decades, its physiological and pathological implications are just beginning to be recognized. D 2003 Elsevier Science B.V. All rights reserved. Keywords: Methylamine; Formaldehyde; Methylglyoxal; SSAO; VAP-1; Diabetes
1. Introduction Semicarbazide-sensitive amine oxidase (SSAO) is a group of enzymes containing copper and quinone and sensitive to semicarbazide. The enzyme is present either as membrane or soluble forms located in the vascular system and adipocytes [1]. It has been shown that this enzyme may be involved in detoxifying xenobiotic amines [2], regulating glucose uptake [3], affecting cell adhesion, that is, leukocyte trafficking [4] and may also be linked to angiogenesis [5]. Increased serum SSAO activities were found in patients with diabetic complications, vascular disorders [6 –11] and heart disease [12,13]. Interestingly, SSAO-mediated deamination of methylamine and aminoacetone leads to production of toxic formaldehyde and methylglyoxal, respectively [14]. These toxic products may * Corresponding author. Tel.: +1-306-966-8816; fax: +1-306-9668830. E-mail address: [email protected] (P.H. Yu).
be responsible, at least in part, for protein cross-linkage, oxidative stress and cytotoxicity. This seems to be consistent with several of the existing hypotheses for vascular damage and advanced protein aggregation related to vascular disorders, such as diabetic complications, atherosclerosis, Alzheimer’s disease and aging.
2. SSAO-catalyzed oxidative deamination of endogenous substrate methylamine and aminoacetone Methylamine [15 –17] and aminoacetone [18 – 20] are readily deaminated by SSAO (EC 1.4.3.6) in vitro and in vivo. Formaldehyde and methylglyoxal, respectively, as well as hydrogen peroxide and ammonia are produced. SSAO
CH3 NH2 þ O2 þ H2 O ! HCHO þ H2 O2 þ NH3 CH3 CO CH2 NH2 þ O2 þ H2 O
1570-9639/03/$ - see front matter D 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S1570-9639(03)00101-8
!CH3 COCHO þ H2 O2 þ NH3
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A large quantity of methylamine was found in urine [21,22]. It is also present in blood [23,24] and tissues [25 – 27]. Methylamine can be derived from several metabolic reactions, such as the deamination of adrenaline [28 – 30], creatine and creatinine (via sarcosine) [31,32] and choline [33]. It can be ingested from food and drink or inhaled from cigarette smoke [34]. When rats are treated with SSAO inhibitors, their urinary excretion of methylamine is increased several fold [27,35]. Direct detection of endogenous formaldehyde or methylglyoxal (i.e. as a product of an SSAO-catalyzed reaction) is only partly useful, because these aldehydes rapidly interact with cellular constituents or are metabolized. Tracing residual radioactivity after the administration of 14C-methylamine in the presence or absence of specific SSAO inhibitors confirmed the conversion of methylamine to formaldehyde, and the irreversible interaction of formaldehyde with tissue components (primarily proteins) in vivo [36]. Aminoacetone is endogenously present and is derived from glycine or threonine [37]. We recently developed a method for the determination of aminoacetone levels in tissues and urine using an HPLC method [38]. Methylglyoxal was found to be significantly increased in the blood of diabetic patients [39] and is considered to cause advanced protein glycation and diabetic complications [40].
3. Cytotoxicity of formaldehyde, methylglyoxal and H 2O 2 Formaldehyde is an extremely reactive chemical. It interacts with monoamines or amides to form methylene bridges and produces irreversibly covalently cross-linked complexes with proteins and with single-stranded DNA [41,42]. It is extremely cytotoxic and has been considered to be potentially carcinogenic, making it a subject of major environmental concern [42,43]. Formaldehyde has been thought to be metabolized by formaldehyde dehydrogenase to formic acid and detoxified intracellularly in the presence of NAD+ and reduced glutathione (GSH) [44,45]. However, the Km with respect to free formaldehyde is rather high (0.2 –0.5 mM). It seems to be uncertain, whether or not formaldehyde is metabolized via this enzyme, because the endogenous formaldehyde concentrations are much lower [46]. The interaction between endogenous formaldehyde and proteins in vivo is probably rather prominent. It is also known that serum does not contain formaldehyde dehydrogenase [47]. Formaldehyde in blood therefore cannot be metabolized unless it is first transported into erythrocytes [48]. This is a very important point with respect to formaldehyde-induced toxicity to blood vessels (see below). Methylglyoxal is also a bioactive aldehyde. Its cytotoxicity has been previously reported [49] and it can quickly cross-link proteins [50]. Increased protein cross-linkage has been recognized to be involved in the aging process, which seems to be related to chronic vascular disorders.
H2O2 is a major reactive oxygen species, which is also generated in SSAO-catalyzed deaminations. In the presence of transition metals, H2O2 can be converted to toxic hydroxyl free radicals via the Fenton reaction (H2O2+ Fe2+!*OH + OH + Fe3 +) and has been implicated in several diseases [51]. Interestingly, free radicals can be generated from formaldehyde in the presence of hydrogen peroxide (2HCHO +H2O2 ! 2HU*CMO + 2H2O) under alkaline conditions [52]. In the presence of free amino group along with formaldehyde and H2O2, however, both excited formaldehyde and singlet oxygen are generated even under physiological pH [53]. It is intriguing that both formaldehyde and H2O2 are simultaneously formed from oxidative deamination of methylamine. It is reasonable to suggest that oxidative stress can be induced by an SSAO-mediated reaction, resulting in the oxidation of LDL and glycoxidation of proteins.
4. Pathological implications of increased SSAO-catalyzed deamination Allylamine, an industrial chemical, can cause extensive and progressive vascular and myocardial lesions in several mammalian species [54]. The vascular damage induced by allylamine exhibits features very similar to those seen in human atherosclerosis. Allylamine (CH2MCHCH2NH2) is converted by vascular SSAO to the toxic acrolein (CH2M CHCHO) in vitro and in vivo [55]. The vascular toxicity of allylamine can be completely prevented by the SSAO inhibitor semicarbazide in experimental animals [56]. Unlike allylamine, methylamine and aminoacetone are present endogenously. Because both SSAO and the amine substrates are present in circulating blood, it is conceivable that the deamination of methylamine and aminoacetone can occur in blood. The products, formaldehyde, methylglyoxal and H2O2, if not detoxified, could then become harmful to the blood vessels. Methylamine, in the presence of SSAO, is indeed toxic to human endothelial cells and forms patch-like lesions [57]. Our recent results have shown that chronic administration of methylamine alters urinary excretion of prorenin, suggesting that the kidney may be damaged [36]. Our recent observation indicates that chronic methylamine treatment increases fatty streaks in C57BL/6 mice fed with a high-cholesterol diet.
5. Increase of serum SSAO activity in different pathological conditions An increase in serum SSAO activity in diabetic patients has been found in different laboratories [6 – 9]. These observations have been further confirmed in juvenile diabetes as well as in both Type I and Type II diabetes [10], and are positively correlated with the severity of diabetic retinopathy [11]. SSAO has also been shown to be increased in
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patients with congestive heart failure [12] and patients with multiple types of cerebral infarct [13]. It has also been shown that SSAO activity is positively correlated with body mass index (BMI) [10]. Interestingly, SSAO activity was also found to be increased in the blood and kidney of diabetic rats (STZ-treated) [58] and sheep (alloxan-treated) [59]. Atherogenesis is a complex process in which the lumen of blood vessels becomes narrowed by cellular and extracellular substances to the point of obstruction. Lesions, often forming at the branch points of arterial blood vessels, progress via fatty streaks, followed by formation of fibrous plaques and finally thrombus formation with deposition of fibrin and platelets [60]. An etiologic model for atherosclerosis, that is, ‘‘response-to-injury’’, has been previously proposed [61,62]. The cause of such an abnormal healing process is unclear. The atherogenesis involves endothelial dysfunction, smooth muscle proliferation and subsequently, architectural disruption. Many hypotheses regarding the mechanism of atherogenesis have been proposed. Hypercholesterolemia, oxidative stress, LDL, LDL receptors, Apo-E, advanced glycation, growth factors, factors affecting hormones, cytokines, cell – cell interaction of monocytes, abnormal lipid metabolism, etc. are all possibly involved [63]. Although rodents are generally very resistant to atherosclerosis, some strains of mice, for example, inbred C57BL/ 6 fed with an atherogenic high-cholesterol diet, will develop atherosclerotic lesions [64,65]. C57BL/6 mice, which are known to be vulnerable to atherosclerosis, exhibit significantly higher SSAO activity [66]. These findings suggest that SSAO-mediated deamination is probably (at least in part) involved in atherogenesis and vascular disorders. KKAy mice is a strain possessing features closely resembling those of non-insulin-dependent diabetes mellitus (NIDDM). It has recently been found that both selective mechanism-based SSAO inhibitor and amino-guanidine effectively reduced the oxidative stress, as shown by reduction of malondialdehyde excretion, albuminuria and the number of atherosclerotic lesions in KKAy mice fed with high-cholesterol diet over a period of 16 weeks treatment [67]. Rabbits are well known to be vulnerable to atherosclerosis. Interestingly, rabbits, like humans, exhibit very high SSAO activity. Increased SSAO-mediated deamination could be involved in the cascade of atherogenesis related to diabetic complications or other disorders. Formaldehyde (which cross-links proteins) and H2O2 (which enhances oxidative stress) derived from methylamine deamination (e.g. due to persistent high blood SSAO levels in diabetes) or increased availability of substrates can induce chronic stress, which repeatedly damage endothelial cells. It is interesting to note that such chronic formaldehyde and oxidative stress does not necessarily cause acute endothelial damage. It may induce protein cross-linkage of long-lasting structural proteins, such as collagen. The rigidity of these proteins will be gradually and cumulatively increased until dysfunction occurs. The compartment, in
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which endogenous formaldehyde is produced, is very important. It is likely that SSAO-mediated production of formaldehyde would be hazardous, because it cannot be readily detoxified. It is also interesting to note that bound SSAO was found to be facing out of the plasma membrane of vascular smooth muscle [1], suggesting that not only circulating but also tissue-bound SSAO are capable of deaminating circulating amines. SSAO is known to be selectively located in the plasma membrane of vascular smooth muscle and endothelial cells, such as blood vessels [68 –70], retina and brain microvessels [71] and cartilage [72]. These tissues are vulnerable to diabetic complications. Interestingly, such a compartment for SSAO is consistent with other independent findings, where SSAO had been identified as a vascular adhesion protein-1 (VAP-1), which is related to leukocyte trafficking and inflammation (see Section 7). It is unclear how serum and kidney SSAO activity is increased in diabetic, cerebral infarct or atherosclerotic patients. It could be a result of compensatory up-regulation (i.e. in response to increased substrates), or may be a consequence of vascular damage due to the illness, namely, SSAO is released into the blood stream from damaged SSAO-rich tissues, such as the vascular smooth muscle cells. VAP-1, which is the same protein as SSAO, is upregulated in response to inflammation [73]. The increase in serum SSAO in diabetic patients may be a result of increased expression of SSAO. Increased deamination of methylamine and/or aminoacetone by SSAO would increase toxic aldehyde levels in blood, enhance oxidative stress and cause more vascular injury and inflammation in the blood vessels. Damage in the vascular system would cause more SSAO leakage and this would create a vicious cytotoxic cycle contributing toward angiopathy.
6. Methylamine, aminoacetone and their aldehyde metabolites Urinary excretion of methylamine in uremic patients is dramatically reduced [22]. This finding is consistent with an earlier report that blood methylamine levels in uremic patients is approximately 20-fold higher than in the control populations [24]. The methylamine clearance seems to be impaired in these patients. Furthermore, accumulation of creatinine and creatine due to renal failure may also lead to increased formation of methylamine via sarcosine. Nephropathy (i.e. microangiopathy in the renal glomeruli) is a major complication associated with diabetes, and cardiovascular disorders are a common problem for uremic patients. The ‘‘flooding’’ of methylamine in the blood, where SSAO is also present, may produce a chronic ‘‘aldehyde and oxidative’’ stress condition in favor of angiopathy. Methylglyoxal, the deaminated product of aminoacetone, is increased 2- to 4-fold in the blood and kidneys
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of diabetics [74]. Methylglyoxal was observed to form protein adducts, such as with albumin [75], and this reaction was blocked by aminoguanidine [76]. This adduct formation has been claimed to be involved in the pathogenesis of diabetes mellitus [39,50,77]. The results are also consistent with the notion that increased SSAO-catalyzed deamination could be involved in pathogenesis in these patients. Cardiovascular and cerebrovascular disorders are well known to be associated with cigarette smoking and stressrelated behaviors. Adrenaline and nicotine have been shown to cause an increase in methylamine, which would subsequently be converted to formaldehyde by SSAO and perhaps related to angiopathy [30,78].
7. SSAO is identical to VAP-1; its relevance to inflammation SSAO, a copper enzyme containing TOPA as cofactor, was discovered several decades ago. The enzyme has been cloned and its primary structure has been characterized [79,80]. Interestingly, the sequence of another protein called VAP-1 has been subsequently found to be identical to SSAO [81]. Indeed, VAP-1 has been shown to be capable of deaminating amines. Its distribution is also very similar to that of SSAO. The discovery was completely independent from SSAO research. VAP-1, which contains polysialic acid, induces cell adhesion and regulates lymphocyte trafficking [82]. VAP-1 is involved in granulocyte extravasation [83] and its level has been shown to be upregulated during inflammation [73]. It is intriguing that a single protein possesses such completely different functions. It remains to be established whether or not the two functions of this protein may act in a concerted fashion. It is perhaps interesting to note that formaldehyde, the deaminated product of methylamine, can induce inflammation
and has been used as an agent to elicit inflammation (i.e. arthritis).
8. Involvement of SSAO-mediated deamination in glucose transport in the adipocytes SSAO has been found to be involved in the regulation of GLUT-4 in isolated rat adipose cells [3] and in the 3T3 F422A cell line [84]. Benzylamine, an SSAO substrate, caused a marked stimulation of glucose uptake in adipocytes in the presence of a low concentration of vanadate [85]. This induction was blocked by SSAO inhibitor semicarbazide or catalase, suggesting that hydrogen peroxide production coupled with SSAO-mediated deamination plays a crucial regulatory role. It is interesting to note that SSAO is primarily present and able to produce hydrogen peroxide on the outer plasma membrane. SSAO has been claimed to play a regulatory role in glucose uptake in adipocytes. Interestingly, SSAO-mediated deamination also mimics other insulin-like actions such as on the signal transduction pathway [85], lipid metabolism [86] and differentiation of adipocytes [84,87,88]. Recently, it has been shown that glucose uptake in cultured differentiated vascular smooth muscle cells was also enhanced by SSAO substrates [89]. Benzylamine in combination with vanadate was capable of reducing the blood glucose levels in STZ-induced diabetic rat [90]. SSAO-mediated deamination could potentially play an important role in regulating glucose uptake and adipocytes differentiation and has significant physiological and pathological implications.
9. Hypothesis SSAO, an enzyme selectively located in vascular tissues, catalyzes the deamination of methylamine and aminoace-
Scheme 1. Hypothesis: Involvement of SSAO-mediated deamination in vascular disorders.
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tone. Formaldehyde and methylglyoxal as well as H2O2 and ammonia are produced respectively, which are all potentially cytotoxic. An increase in SSAO-mediated deamination may be related to atherosclerosis, obesity and diabetic complications. The following scheme summarizes the hypothesis (Scheme 1) . Both formaldehyde and methylglyoxal are capable of cross-linking proteins and enhancing advanced glycation. This will alter functional and structural proteins, which can initiate acute damage and cause chronic hardening of blood vessels, subsequently leading to atherosclerosis. Hydrogen peroxide increases oxidative stress and is related to atherogenesis. Increased SSAO-catalyzed deamination in the adipocytes may enhance glucose uptake and lipogenesis and is potentially involved in causing unwanted weight gain.
[10]
[11]
[12]
[13] [14]
[15]
Acknowledgements [16]
The authors thank the Canadian Institute of Health, Heart and Stroke Foundation, and Saskatchewan Health for their continuous financial support.
[17]
[18]
References [1] B.A. Callingham, A.E. Crosbie, B.A. Rous, Some aspects of the pathophysiology of semicarbazide-sensitive amine oxidase enzymes, in: P.H. Yu, K.F. Tipton, A.A. Boulton (Eds.), Current Neurochemical and Pharmacological Aspects of Biogenic Amines: Their Function, Oxidative Deamination and Inhibition, Elsevier, Amsterdam, 1995, pp. 305 – 321. [2] J. Elliott, B.A. Callingham, D.F. Sharman, The influence of amine metabolizing enzymes on the pharmacology of tyramine in the isolated perfused mesenteric arterial bed of rat, Br. J. Pharmacol. 98 (1989) 515 – 522. [3] G. Enrique-Tarancon, L. Marti, N. Morin, J.M. Lizcano, M. Unzeta, L. Sevilla, M. Camps, M. Palacin, X. Testar, C. Carpene, A. Zorzano, Role of semicarbazide-sensitive amine oxidase on glucose transport and GLUT4 recruitment to the cell surface in adipose cells, J. Biol. Chem. 273 (1998) 8025 – 8032. [4] M. Salmi, J. Hellman, S. Jalkanen, The role of two distinct endothelial molecules, vascular adhesion protein-1 and peripheral lymph node addressin, in the binding of lymphocyte subsets to human lymph nodes, J. Immunol. 160 (1998) 5629 – 5636. [5] S.D. Langford, M.B. Trent, A. Balakumaran, P.J. Boor, Developmental vasculotoxicity associated with inhibition of semicarbazide-sensitive amine oxidase, Toxicol. Appl. Pharmacol. 155 (1999) 237 – 244. [6] N. Tryding, S.E. Nilsson, G. Tufvesson, R. Berg, S. Carlstrom, B. Elmfors, J.E. Nilsson, Physiological and pathological influences on serum monoamine oxidase level, Scand. J. Clin. Lab. Invest. 23 (1969) 79 – 84. [7] S.E. Nilsson, N. Tryding, G. Tufvesson, Serum monoamine oxidase in diabetes mellitus and some other internal diseases, Acta Med. Scand. 184 (1968) 105 – 108. [8] C.T. Yuen, D. Easton, K. Misch, E.L. Rhodes, Increased activity of serum amine oxidase in granuloma annulare, necrobiosis lipoidics and diabetes, Br. J. Dermatol. 11 (1987) 643 – 649. [9] F. Boomsma, F.H.M. Derks, A.H. van den Meiracker, A. Man in’tVeld, M.A.D.H. Schalekamp, Plasma semicarbazide-sensitive
[19]
[20]
[21] [22]
[23] [24]
[25]
[26] [27]
[28]
[29]
[30]
197
amine oxidase activity is elevated in diabetes mellitus and correlates with glycosylated haemoglobin, Clin. Sci. 88 (1995) 675 – 679. H. Garpenstrand, J. Ekblom, L.B. Backlund, L. Oreland, U. Rosenqvist, Elevated plasma semicarbazide-sensitive amine oxidase (SSAO) activity in Type 2 diabetes mellitus complicated by retinopathy, Diabet. Med. 16 (1999) 514 – 521. Z. Me´sza´ros, T. Szombathy, L. Raimondi, I. Karadi, L. Romics, K. Magyar, Elevated serum semicarbazide-sensitive amine oxidase activity in non-insulin-dependent diabetes mellitus: correlation with BMI and serum triglyceride, Metab. Clin. Exp. 48 (1999) 113 – 117. F. Boomsma, D.J. van Veldhuisen, P.J. de Kam, A.J.M. in’t Veld, A. Mosterd, K.I. Lie, M.A.D.H. Schalekamp, Plasma semicarbazide-sensitive amine oxidase is elevated in patients with congestive heart failure, Cardiovasc. Res. 33 (1997) 387 – 391. F. Ishizaki, Plasma benzylamine oxidase activity in cerebrovascular disease, Eur. Neurol. 30 (1990) 104 – 107. P.H. Yu, Deamination of methylamine and angiopathy; toxicity of formaldehyde, oxidative stress and relevance to protein glycoxidation in diabetes, J. Neural Transm., Suppl. 52 (1996) 201 – 216. E. Precious, C.E. Gunn, G.A. Lyles, Deamination of methylamine by semicarbazide-sensitive amine oxidase in human umbilical artery and rat aorta, Biochem. Pharmacol. 37 (1988) 707 – 713. P.H. Yu, Oxidative deamination of aliphatic amines by rat aorta semicarbazide-sensitive amine oxidase, J. Pharm. Pharmacol. 42 (1990) 882 – 884. P.J. Boor, M.B. Trent, G.A. Lyles, M. Tao, G.A.S. Ansari, Methylamine metabolism to formaldehyde by vascular semicarbazide-sensitive amine oxidase, Toxicology 73 (1992) 251 – 258. N.P. Kalapos, T. Garzo, F. Antoni, S. Mardl, Accumulation of S-Dlactolylglutathione and transient decrease of glutathione level caused by methylglyoxal load in isolated hepatocytes, Biochim. Biophys. Acta 1135 (1992) 159 – 164. G.A. Lyles, J. Chalmers, The metabolism of aminoacetone to methylglyoxal by semicarbazide-sensitive amine oxidase in human umbilical artery, Biochem. Pharmacol. 31 (1992) 1417 – 1424. G.A. Lyles, Substrate-specificity of mammalian tissue-bound semicarbazide-sensitive amine oxidase, Prog. Brain Res. 106 (1995) 293 – 303. K. Blau, Chromatographic methods for the study of amines from biological material, Biochem. J. 80 (1961) 193 – 200. P.H. Yu, R.F. Dyck, Impairment of methylamine clearance in uremic patients and its nephropathological implications, Clin. Nephrol. 49 (1998) 299 – 302. A.M. Asatoor, D.N.S. Kerr, Amines in blood and urine in relation to liver disease, Clin. Chim. Acta 6 (1961) 149 – 156. S. Baba, Y. Watanabe, F. Gejyo, M. Arakwa, High-performance liquid chromatographic determination of serum aliphatic amines in chronic renal failure, Clin. Chim. Acta 136 (1984) 49 – 56. A.D. Smith, J.B. Jepson, Chromatography of urinary and tissue amines and amino alcohols as 2,4-dinitrophenyl derivatives prepared with 2-nitrobenzene-sulfonic acid, Anal. Biochem. 18 (1967) 36 – 45. R. Nixon, Volatile amines in mouse brain: a radioassay with picogram sensitivity, Anal. Biochem. 48 (1972) 460 – 470. G.A. Lyles, S.A. McDougall, The enhanced daily excretion of urinary methylamine in rats treated with semicarbazide or hydralazine may be related to the inhibition of semicarbazide-sensitive amine oxidase activities, J. Pharm. Pharmacol. 41 (1989) 97 – 100. R.W. Schayer, L.R. Smiley, H.E. Kaplan, The metabolism of epinephrine containing isotopic carbon, J. Biol. Chem. 198 (1952) 545 – 551. M.S. Dar, P.L. Morselli, E.R. Bowman, The enzymatic systems involved in the mammalian metabolism of methylamine, Gen. Pharmacol. 16 (1985) 557 – 560. P.H. Yu, C.T. Lai, D.M. Zuo, Formation of formaldehyde from adrenaline in vivo; a potential risk factor endothelial damage, Neurochem. Res. 22 (1997) 615 – 620.
198
P.H. Yu et al. / Biochimica et Biophysica Acta 1647 (2003) 193–199
[31] J.D. Jones, P.C. Burnett, Creatinine metabolism and toxicity, Kidney Int. 7 (1975) S294 – S298. [32] P.H. Yu, Y.L. Deng, Potential cytotoxic effect of chronic administration of creatine, a nutrition supplement to augment athletic performance, Med. Hypotheses 54 (1999) 726 – 728. [33] S.H. Zeisel, J.S. Wishnok, J.K. Blusztajn, Formation of methylamines from ingested choline and lecithin, J. Pharmacol. Exp. Ther. 225 (1983) 320 – 324. [34] US Dept Health and Human Services, Constituents of tobacco smoke, USPHS Publication No. 82-50179 (1982) 322. [35] P.H. Yu, D.M. Zuo, Aminoguanidine inhibits semicarbazide-sensitive amine oxidase activity; implication for advanced glycation and angiopathy in diabetes, Diabetologia 363 (1997) 1243 – 1250. [36] P.H. Yu, D.M. Zuo, Formaldehyde produced endogenously via deamination of methylamine; a potential risk factor for initiation of endothelial injury, Atherosclerosis 120 (1996) 189 – 197. [37] M.I. Bird, P.B. Nunn, L.A.J. Lord, Formation of glycine and aminoacetone from L-threonine by rat liver mitochondria, Biochim. Biophys. Acta 802 (1984) 229 – 236. [38] Y.L. Deng, P.H. Yu, Assessment of the deamination of aminoacetone, an endogenous substrate for semicarbazide-sensitive amine oxidase, Anal. Biochem. 270 (1999) 97 – 102. [39] P.J. Thornalley, Methylglyoxal, glyoxalases and the development of diabetic complications, Amino Acids 6 (1994) 15 – 23. [40] E.W. Westwood, A.C. McLellan, P.J. Thornalley, Receptor-mediated endocytic uptake of methylglyoxal-modified serum albumin, J. Biol. Chem. 269 (1994) 32293 – 32298. [41] H.M. Bolt, Experimental toxicology of formaldehyde, J. Cancer Res. Clin. Oncol. 13 (1987) 305 – 309. [42] H.D. Heck, M. Casanova, T.B. Starr, Formaldehyde toxicity—new understanding, Toxicology 20 (1990) 397 – 426. [43] J.E. Gibson (Ed.), Formaldehyde Toxicity, Hemisphere Publ., Washington, 1983. [44] J.R. Cooper, M.M. Kini, Editorial biochemical aspects of methanol poisoning, Biochem. Pharmacol. 11 (1962) 405 – 416. [45] S. Tsuboi, M. Kawase, A. Takaka, M. Hirmatus, Y. Wada, Y. Kawakami, M. Ikeka, S. Ohmori, Purification and characterization of formaldehyde dehydrogenase from rat liver cytosol, J. Biochem. 111 (1992) 465 – 471. [46] H.D. Heck, M. Casanova, Isotope effects and their implications for the covalent binding of inhaled [3H]-and [14C]-formaldehyde in the rat nasal mucosa, Toxicol. Appl. Pharmacol. 89 (1987) 123 – 130. [47] A. Helander, O. Tottmar, Metabolism of biogenic aldehydes in isolated human blood cells, platelets and in plasma, Biochem. Pharmacol. 36 (1987) 1077 – 1082. [48] G.N. Malorny, N. Rietbrock, M. Schneider, The oxidation of formaldehyde to formic acid in the blood and contribution to the metabolism of formaldehyde, Naunyn-Schmiedeberg’s Arch. Exp. Pathol. Pharmakol. 250 (1965) 419 – 436. [49] L.G. Egyud, A. Szent-Gyorgyi, Cancer static action of methylglyoxal, Science 160 (1968) 1140. [50] R.H. Nagaraj, I.N. Shipanova, F.M. Faust, Protein cross-linking by the Mailard reaction. Isolation, characterization and in vivo detection of a lysine – lysine cross-link derived from methylglyoxal, J. Biol. Chem. 271 (1996) 19338 – 19345. [51] H. Sies, Oxidative Stress; Oxidants and Antioxidants, Academic Press, London, 1991. [52] K. Lichszteld, L. Kruk, Singlet molecular oxygen in formaldehyde oxidation, Z. Phys. Chem. (N. F.) 108 (1977) 167 – 172. [53] L. Tre´zl, J. Pipek, Formation of exited formaldehyde in model reactions simulating real biological system, J. Mol. Struct. 170 (1988) 213 – 223. [54] P.J. Boor, R.M. Hysmith, Allylamine cardiovascular toxicity, Toxicology 44 (1987) 129 – 144. [55] T.J. Nelson, P.J. Boor, Allylamine cardiotoxicity: IV. Metabolism to acrolein by cardiovascular tissues, Biochem. Pharmacol. 31 (1982) 509 – 514.
[56] P.J. Boor, T.J. Nelson, Allylamine cardiotoxicity: III. Protection by semicarbazide and in vivo derangements of monoamine oxidase, Toxicology 18 (1980) 87 – 102. [57] P.H. Yu, D.M. Zuo, Methylamine, a potential endogenous toxin for vascular tissues: formation of formaldehyde via enzymatic deamination and the cytotoxic effects on endothelial cells, Diabetes 42 (1993) 594 – 603. [58] B.E. Hayes, D.E. Clarke, Semicarbazide-sensitive amine oxidase activity in streptozotocin diabetic rats, Res. Commun. Chem. Pathol. Pharmacol. 69 (1990) 71 – 83. [59] J. Elliott, A.L. Fowden, B.A. Callingham, D.F. Sharman, M. Silver, Physiological and pathological influences on sheep blood plasma amine oxidase: effect of pregnancy and experimental alloxan-induced diabetes mellitus, Res. Vet. Sci. 50 (1991) 334 – 339. [60] J.L. Breslow, Mouse models of atherosclerosis, Science 272 (1996) 685 – 688. [61] R. Ross, The pathogenesis of atherosclerosis—an update, N. Engl. J. Med. 314 (1986) 488 – 500. [62] R. Ross, L. Harker, Hyperlipidemia and atherosclerosis; chronic hyperlipidemia initiates and maintains lesion by endothelial cell desquamation and lipid accumulation, Science 193 (1976) 1094 – 1100. [63] M. Sanders, Molecular and cellular concepts in atherosclerosis, Pharmacol. Ther. 61 (1994) 109153. [64] B. Paigen, A. Morrow, C. Brandon, D. Mitchell, P.A. Holmes, Variation in susceptibility to atherosclerosis among inbred strains of mice, Atherosclerosis 57 (1985) 65 – 73. [65] B. Paigen, B.Y. Ishida, J. Verstuyft, R.B. Winter, D. Albee, Atherosclerosis susceptibility differences among progenitors of recombinant inbred strains of mice, Arteriosclerosis 10 (1990) 316 – 323. [66] P.H. Yu, Y.L. Deng, Endogenous formaldehyde and vulnerability of atherosclerosis: involvement of semicarbazide-sensitive amine oxidase-mediated methylamine turnover, Atherosclerosis 140 (1999) 357 – 363. [67] P.H. Yu, M. Wang, Y.L. Deng, H. Fan, L. Shira-Bock, Effect of semicarbazide-sensitive amine oxidase inhibitor on atherogenesis in KKAy diabetic mice fed with high cholesterol diet, Diabetologia 45 (2002) 1255 – 1262. [68] M. Wibo, A.T. Duong, T. Godfraind, Subcellular location of semicarbazide-sensitive amine oxidase in rat aorta, Eur. J. Biochem. 112 (1980) 87 – 94. [69] R. Lewinsohn, Amine oxidase in human blood vessels and non-vascular smooth muscle, J. Pharm. Pharmacol. 33 (1981) 569 – 575. [70] G.A. Lyles, I. Singh, Vascular smooth muscle cells: a major source of the semicarbazide-sensitive amine oxidase of the rat aorta, J. Pharm. Pharmacol. 37 (1985) 637 – 643. [71] D.M. Zuo, P.H. Yu, Semicarbazide-sensitive amine oxidase and monoamine oxidase in rat brain microvessels, meninges, retina and eye sclera, Brain Res. Bull. 33 (1994) 307 – 311. [72] G.A. Lyles, K.H. Bertie, Properties of a semicarbazide-sensitive amine oxidase in rat articular cartilage, Pharmacol. Toxicol. (Suppl.) 1 (1987) 33. [73] R. Kurkijarvi, D.H. Adams, R. Leino, T. Mottonen, S. Jalkanen, M. Salmi, Circulating form of human vascular adhesion protein-1 (VAP-1): increased serum levels in inflammatory liver diseases, J. Immunol. 161 (1998) 1549 – 1557. [74] A.C. McLellan, S.A. Phillips, P.J. Thornalley, The assay of methylglyoxal in biological systems by derivatization with diamno-4,5-dimethoxybenzene, Anal. Biochem. 206 (1992) 17 – 23. [75] T.W.C. Lo, M.E. Westwood, A.C. McLellan, T. Selwood, P.J. Thornalley, Binding and modification of proteins by methylglyoxal under physiological conditions, J. Biol. Chem. 269 (1994) 32299 – 32305. [76] T.W.C. Lo, T. Selwood, P.J. Thornalley, The reaction of methylglyoxal with aminoguanidine under physiological conditions and prevention of methylglyoxal binding to plasma proteins, Biochem. Pharmacol. 48 (1994) 1865 – 1870. [77] A.C. McLellan, P.J. Thornalley, J. Benn, P.H. Sonksen, Glyoxalase
P.H. Yu et al. / Biochimica et Biophysica Acta 1647 (2003) 193–199
[78]
[79]
[80]
[81]
[82] [83]
[84]
[85]
system in clinical diabetes mellitus and correlation with diabetic complications, Clin. Sci. Colch. 87 (1994) 21 – 29. P.H. Yu, Increase of formation of methylamine and formaldehyde in vivo after administration of nicotine and potential cytotoxicity, Neurochem. Res. 23 (1998) 1207 – 1212. N.J. Morris, A. Durett, R. Aebersold, S.A. Ross, S.R. Keller, G.E. Lienhard, Membrane amine oxidase cloning and identification as a major protein in the adipocyte plasma membrane, J. Biol. Chem. 272 (1997) 9388 – 9392. X. Zhang, W.S. McIntire, Cloning and sequencing of a copper-containing, topa quinone-containing monoamine oxidase from human placenta, Gene 179 (1996) 279 – 286. D.J. Smith, M. Salmi, P. Bono, J. Hellman, T. Leu, S. Jalkanen, Cloning of vascular adhesion protein-1; reveals a novel multifunctional adhesion molecule, J. Exp. Med. 188 (1998) 17 – 27. M. Salmi, S. Jalkanen, VAP-1: an adhesin and an enzyme, Trends Immunol. 22 (2001) 211 – 216. S. Tohka, M. Laukkanen, S. Jalkanen, M. Salmi, Vascular adhesion protein-1 (VAP-1) functions as a molecular brake during granulocyte rolling and mediates recruitment in vivo, FASEB J. 15 (2001) 373 – 382. E. Fontana, J. Boucher, L. Marti, J.M. Lizcano, X. Testar, A. Zorzano, C. Carpene, Amine oxidase substrates mimic several of the insulin effects on adipocyte differentiation in 3T3 F442A cells, Biochem. J. 356 (2001) 769 – 777. G. Enrique-Tarancon, I. Castan, N. Morin, L. Marti, A. Abella, M. Camps, R. Casamitjana, M. Palacin, X. Testar, E. Degerman, C. Car-
[86]
[87]
[88]
[89]
[90]
199
pene, A. Zorzano, Substrates of semicarbazide-sensitive amine oxidase co-operate with vanadate to stimulate tyrosine phosphorylation of insulin-receptor-substrate proteins, phosphoinositide 3-kinase activity and GLUT4 translocation in adipose cells, Biochem. J. 350 (2000) 171 – 180. N. Morin, J.M. Lizcano, E. Fontana, L. Marti, F. Smih, P. Rouet, D. Prevot, A. Zorzano, M. Unzeta, C. Carpene, Semicarbazide-sensitive amine oxidase substrates stimulate glucose transport and inhibit lipolysis in human adipocytes, J. Pharmacol. Exp. Ther. 297 (2001) 563 – 572. N. Mercier, M. Moldes, K. El-Hadri, B. Feve, Semicarbazide-sensitive amine oxidase activation promotes adipose conversion of 3T3-L1 cells, Biochem. J. 358 (2001) 335 – 342. N. Morin, J.M. Lizcano, E. Fontana, L. Marti, F. Smih, P. Rouet, D. Prevot, A. Zorzano, M. Unzeta, C. Carpene, Semicarbazide-sensitive amine oxidase substrates stimulate glucose transport and inhibit lipolysis in human adipocytes, J. Pharmacol. Exp. Ther. 297 (2001) 563 – 572. K. El-Hadri, M. Moldes, N. Mercier, M. Andreani, J. Pairault, B. Feve, Semicarbazide-sensitive amine oxidase in vascular smooth muscle cells: differentiation-dependent expression and role in glucose uptake, Arterioscler. Thromb. Vasc. Biol. 22 (2002) 89 – 94. L. Marti, A. Abella, C. Carpene, M. Palacin, X. Testar, A. Zorzano, Combined treatment with benzylamine and low dosages of vanadate enhances glucose tolerance and reduces hyperglycemia in streptozotocin-induced diabetic rats, Diabetes 50 (2001) 2061 – 2068.