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Lipid, Oxidative and Inflammatory Profile and Alterations in the Enzymes Paraoxonase and Butyrylcholinesterase in Plasma of Patients with Homocystinuria Due CBS Deficiency: The Vitamin B12 and Folic Acid Importance

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Abstract

Cystathionine-β-synthase (CBS) deficiency is the main cause of homocystinuria. Homocysteine (Hcy), methionine, and other metabolites of Hcy accumulate in the body of affected patients. Despite the fact that thromboembolism represents the major cause of morbidity in CBS-deficient patients, the mechanisms of cardiovascular alterations found in homocystinuria remain unclear. In this work, we evaluated the lipid and inflammatory profile, oxidative protein damage, and the activities of the enzymes paraoxonase (PON1) and butyrylcholinesterase (BuChE) in plasma of CBS-deficient patients at diagnosis and during the treatment (protein-restricted diet supplemented with pyridoxine, folic acid, betaine, and vitamin B12). We also investigated the effect of folic acid and vitamin B12 on these parameters. We found a significant decrease in HDL cholesterol and apolipoprotein A1 (ApoA-1) levels, as well as in PON1 activity in both untreated and treated CBS-deficient patients when compared to controls. BuChE activity and IL-6 levels were significantly increased in not treated patients. Furthermore, significant positive correlations between PON1 activity and sulphydryl groups and between IL-6 levels and carbonyl content were verified. Moreover, vitamin B12 was positively correlated with PON1 and ApoA-1 levels, while folic acid was inversely correlated with total Hcy concentration, demonstrating the importance of this treatment. Our results also demonstrated that CBS-deficient patients presented important alterations in biochemical parameters, possibly caused by the metabolites of Hcy, as well as by oxidative stress, and that the adequate adherence to the treatment is essential to revert or prevent these alterations.

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References

  • Aksenov MY, Markesbery WR (2001) Changes in thiol content and expression of glutathione redox system genes in the hippocampus and cerebellum in Alzheimer’s disease. Neurosci Lett 302:141–145

    Article  CAS  PubMed  Google Scholar 

  • Aviram M, Billecke S, Sorenson R, Bisgaier CL, Newton RS, Rosenblat M et al (1998) Paraoxonase active site required for protection against LDL oxidation involves its free sulfhydryl group and is different than that required for its arylesterase/paraoxonase activities: selective action of human paraoxonase allozymes Q and R. Arterioscler Thromb Vasc Biol 18:1617–1624

    Article  CAS  PubMed  Google Scholar 

  • Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-die-binding. Anal Biochem 72:248–254

    Article  CAS  PubMed  Google Scholar 

  • da Cunha AA, Ferreira AG, Wyse AT (2010) Increased inflammatory markers in brain and blood of rats subjected to acute homocysteine administration. Metab Brain Dis 25:199–206

    Article  CAS  PubMed  Google Scholar 

  • Dalle-Donne I, Giustarini D, Colombo R, Rossi R, Milzani A (2003) Protein carbonylation in human diseases. Trends Mol Med 9:169–176

    Article  CAS  PubMed  Google Scholar 

  • Darvesh S, Walsh R, Martin E (2007) Homocysteine thiolactone and human cholinesterases. Cell Mol Neurobiol 27:33–48

    Article  CAS  PubMed  Google Scholar 

  • Devlin AM, Lentz SR (2006) ApoA-I : a missing link between homocysteine and lipid metabolism? Circ Res 98:431–433

    Article  CAS  PubMed  Google Scholar 

  • Eckerson HW, Wyte CM, La Du BN (1983) The human serum paraoxonase polymorphism: identification of phenotypes by their response to salts. Am J Hum Genet 35:214–227

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ehara S, Ueda M, Naruko T, Haze K, Itoh A, Otsuka M (2001) Elevated levels of oxidized low density lipoprotein show a positive relationship with the severity of acute coronary syndromes. Circulation 103:1955–1960

    Article  CAS  PubMed  Google Scholar 

  • Ellman GL, Courtney KD, Andres V, Feather-Stone RM (1961) A new and rapid determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–95

    Article  CAS  PubMed  Google Scholar 

  • Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) (2001) Expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). JAMA 285:n19

    Google Scholar 

  • Gori AM, Corsi AM, Fedi S, Gazzini A, Sofi F, Bartali B et al (2005) A proinflammatory state is associated with hyperhomocysteinemia in the elderly. Am J Clin Nutr 82:335–341

    CAS  PubMed  Google Scholar 

  • Gu WJ, Lu JM, Yang GQ, Guo QH, Dou JT, Mu YM et al (2007) Effects of intervention therapy of methylcobalamin and folic acid on plasma homocysteine concentration and homocysteine thiolactonase/paraoxonase activity in patients with type 2 diabetes mellitus. Zhonghua Yi Xue Za Zhi 87:256–258

    CAS  PubMed  Google Scholar 

  • Ishimine N, Usami Y, Nogi S, Sumida T, Kurihara Y, Matsuda K et al (2010) Identification of N-homocysteinylated apolipoprotein AI in normal human sérum. Ann Clin Biochem 47:453–459

    Article  CAS  PubMed  Google Scholar 

  • Jakubowski H (2001) Protein N-homocysteinilation: implications for atherosclerosis. Biomed Pharmacother 55:443–447

    Article  CAS  PubMed  Google Scholar 

  • Jakubowski H (2007) The molecular basis of homocysteine thiolactone-mediated vascular disease. Clin Chem Lab Med 45:1704–1716

    Article  CAS  PubMed  Google Scholar 

  • Jakubowski H (2008) The pathophysiological hypothesis of homocysteine thiolactone-mediated vascular disease. J Physiol Pharmacol 59:155–167

    PubMed  Google Scholar 

  • Jakubowski H, Zhang L, Berdeguez A, Aviv A (2000) Homocysteine thiolactone and protein homocysteinylation in human endothelial cells: implications for atherosclerosis. Circ Res 87:45–51

    Article  CAS  PubMed  Google Scholar 

  • Jakubowski H, Ambrosius WT, Pratt JH (2001) Genetic determinants of homocysteine thiolactonase activity in humans: implications for atherosclerosis. FEBS Lett 491:35–39

    Article  CAS  PubMed  Google Scholar 

  • Jakubowski H, Boers GH, Strauss KA (2008) Mutations in cystathionine β-synthase or methylenetetrahydrofolate reductase gene increase N-homocysteinylated protein levels in humans. FASEB J 22:4071–4076

    Article  CAS  PubMed  Google Scholar 

  • Jiang H, Stabler SP, Allen RH, Maclean KN (2012) Altered expression of apoA-I, apoA-IV and PON-1 activity in CBS deficient homocystinuria in the presence and absence of treatment: possible implications for cardiovascular outcomes. Mol Genet Metab 107:55–65

    Article  CAS  PubMed  Google Scholar 

  • Keating AK, Freehauf C, Jiang H, Brodsky GL, Stabler SP, Allen RH et al (2011) Constitutive induction of pro-inflammatory and chemotactic cytokines in cystathionine beta-synthase deficient homocystinuria. Mol Genet Metab 103:330–337

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Koc A, Cengiz M, Ozdemir ZC, Celik H (2012) Paraoxonase and arylesterase activities in children with iron deficiency anemia and vitamin B12 deficiency anemia. Pediatr Hematol Oncol 29:345–353

    Article  CAS  PubMed  Google Scholar 

  • Levine RL, Garland D, Oliver CN, Amici A, Climent I, Lenz AG et al (1990) Determination of carbonyl content in oxidatively modified proteins. Methods Enzymol 186:464–478

    Article  CAS  PubMed  Google Scholar 

  • Liao D, Tan H, Hui R, Li Z, Jiang X, Gaubatz J et al (2006) Hyperhomocysteinemia decreases circulating highdensity lipoprotein by inhibiting apolipoprotein A-I protein synthesis and enhancing HDL cholesterol clearance. Circ Res 99:598–606

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mack A, Robitzki A (2000) The key role of butyrylcholinesterase during neurogenesis and neural disorders: an antisense-5′-butyrylcholinesterase-DNA study. Prog Neurobiol 60:607–628

    Article  CAS  PubMed  Google Scholar 

  • Magera MJ, Lacey JM, Casetta B, Rinaldo P (1999) Method for the determination of total homocysteine in plasma and urine by stable isotope dilution and electrospray tandem mass spectrometry. Clin Chem 45:1517–1522

    CAS  PubMed  Google Scholar 

  • McCully KS (1969) Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 56:111–128

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mikael LG, Genest J Jr, Rozen R (2006) Elevated homocysteine reduces apolipoprotein A-I expression in hyperhomocysteinemic mice and in males with coronary artery disease. Circ Res 98:564–571

    Article  CAS  PubMed  Google Scholar 

  • Mudd SH, Levy HL, Kraus JP (2001) Disorders of transsulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular basis of inherited disease. McGraw-Hill, New York, pp 2007–2056

    Google Scholar 

  • Nishio E, Watanabe Y (1997) Cigarette smoke extract inhibits plasma paraoxonase activity by modification of the enzyme’s free thiols. Biochem Biophys Res Commun 236:289–293

    Article  CAS  PubMed  Google Scholar 

  • Nuño-Ayala M, Guillén N, Navarro MA, Lou-Bonafonte JM, Arnal C, Gascón S et al (2010) Cysteinemia, rather than homocysteinemia, is associated with plasma apolipoprotein A-I levels in hyperhomocysteinemia: lipid metabolism in cystathionine beta-synthase deficiency. Atherosclerosis 212:268–273

    Article  PubMed  Google Scholar 

  • Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO 3rd, Criqui M et al (2003) Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals From the Centers for Disease Control and Prevention and the American Heart Association. Circulation 107:499–511

    Article  PubMed  Google Scholar 

  • Perla-Kaján J, Jakubowski H (2010) Paraoxonase 1 protects against protein N-homocysteinylation in humans. FASEB J 24:931–936

    Article  PubMed  Google Scholar 

  • Perla-Kaján J, Jakubowski H (2012) Paraoxonase 1 and homocysteine metabolism. Amino Acids 43:1405–1417

    Article  PubMed  Google Scholar 

  • Perla-Kaján J, Twardowski T, Jakubowski H (2007) Mechanisms of homocysteine toxicity in humans. Amino Acids 32:561–572

    Article  PubMed  Google Scholar 

  • Prody CA, Zevin-Sonkin D, Gnatt A, Golberg O, Soreq H (1987) Isolation and characterization of full-length cDNA clones coding for cholinesterase from fetal human tissues. Proc Natl Acad Sci USA 84:3555–3559

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Qujeq D, Omran TS, Hosini L (2001) Correlation between total homocysteine, low density lipoprotein cholesterol and high-density lipoprotein cholesterol in the serum of patients with myocardial infarction. Clin Biochem 34:97–101

    Article  CAS  PubMed  Google Scholar 

  • Santarpia L, Grandone I, Contaldo F, Pasanisi F (2013) Butyrylcholinesterase as a prognostic marker: a review of the literature. J Cachexia Sarcopenia Muscle 4:31–39

    Article  PubMed Central  PubMed  Google Scholar 

  • Singh R, Barden A, Mori T, Beilin L (2001) Advanced glycation end-products: a review. Diabetologia 44:129–146

    Article  CAS  PubMed  Google Scholar 

  • Stefanello FM, Zugno AI, Wannmacher CMD, Wajner M, Wyse ATS (2003) Homocysteine inhibits butyrylcholinesterase activity in rat serum. Metab Brain Dis 18:187–194

    Article  CAS  PubMed  Google Scholar 

  • Stefanello FM, Franzon R, Tagliari B, Wannmacher CMD, Wajner M, Wyse ATS (2005) Reduction of butyrylcholinesterase activity in rat serum subjected to hyperhomocysteinemia. Metab Brain Dis 20:97–103

    Article  CAS  PubMed  Google Scholar 

  • Vanzin CS, Biancini GB, Sitta A, Wayhs CAY, Pereira IN, Rockenbach F et al (2011) Experimental evidence of oxidative stress in plasma of homocystinuric patients: a possible role for homocysteine. Mol Genet Metab 104:112–117

    Article  CAS  PubMed  Google Scholar 

  • Weijun G, Juming L, Guoqing Y, Jingtao D, Qinghua G, Yiming M et al (2008) Effects of plasma homocysteine levels on serum HTASE/PON activity in patients with type 2 diabetes. Adv Ther 25:884–893

    Article  PubMed  Google Scholar 

  • Xiao Y, Zhang Y, Lv X, Su D, Li D, Xia M et al (2011) Relationship between lipid profiles and plasma total homocysteine, cysteine and the risk of coronary artery disease in coronary angiographic subjects. Lipids Health Dis 10:137

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yap S (2003) Classical homocystinuria: vascular risk and its prevention. J Inherit Metab Dis 26:259–265

    Article  CAS  PubMed  Google Scholar 

  • Yap S, Boers GHJ, Wilcken B, Wilcken DEL, Brenton DP, Lee PJ et al (2001) Vascular outcome in patients with homocystinuria due to cystathionine ß-synthase deficiency treated chronically: a multicenter observational study. Arterioscler Thromb Vasc Biol 21:2080–2085

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported in part by grants from CAPES, CNPq, and FIPE/HCPA-Brazil. We thank immensely to the patients included in this study and to the physicians from Serviço de Genética Médica do Hospital de Clínicas de Porto Alegre.

Conflict of interest

The authors declare that there is no conflict of interest disclosure associated with this manuscript.

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Authors and Affiliations

  1. Programa de Pós-Graduação em Ciências Biológicas:Bioquímica da Universidade Federal do Rio Grande do Sul (UFRGS), Ramiro Barcelos 2700, Porto Alegre, RS, 90035-000, Brazil

    Camila Simioni Vanzin, Caroline Paula Mescka, Janaína Kolling, Emilene B. Scherer, Moacir Wajner, Angela T. S. Wyse & Carmen Regla Vargas

  2. Serviço de Genética Médica do Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, Porto Alegre, RS, 90035-903, Brazil

    Camila Simioni Vanzin, Caroline Paula Mescka, Bruna Donida, Tatiane Grazieli Hammerschimidt, Graziela S. Ribas, Moacir Wajner & Carmen Regla Vargas

  3. Instituto Nacional de Saúde Doutor Ricardo Jorge, INSA I.P., Rua Alexandre Herculano 321, 4000-055, Porto, Portugal

    Laura Vilarinho & Célia Nogueira

  4. Departamento de Microbiologa, Instituto de Ciências Básicas e da Saúde, Imunologia e Parasitologia da Universidade Federal do Rio Grande do Sul, Rua Sarmento Leite, 500, Porto Alegre, RS, 90050-170, Brazil

    Adriana Simon Coitinho

  5. Programa de Pós-Graduação em Ciências Farmacêuticas da Universidade Federal do Rio Grande do Sul (UFRGS), Avenida Ipiranga 2752, Porto Alegre, RS, 90610-000, Brazil

    Bruna Donida & Carmen Regla Vargas

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  1. Camila Simioni Vanzin
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  3. Bruna Donida
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Correspondence to Camila Simioni Vanzin or Carmen Regla Vargas.

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Vanzin, C.S., Mescka, C.P., Donida, B. et al. Lipid, Oxidative and Inflammatory Profile and Alterations in the Enzymes Paraoxonase and Butyrylcholinesterase in Plasma of Patients with Homocystinuria Due CBS Deficiency: The Vitamin B12 and Folic Acid Importance. Cell Mol Neurobiol 35, 899–911 (2015). https://doi.org/10.1007/s10571-015-0185-7

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