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PLOS ONE  2012 

Metabolomics Reveals Amino Acids Contribute to Variation in Response to Simvastatin Treatment

DOI: 10.1371/journal.pone.0038386

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Abstract:

Statins are widely prescribed for reducing LDL-cholesterol (C) and risk for cardiovascular disease (CVD), but there is considerable variation in therapeutic response. We used a gas chromatography-time-of-flight mass-spectrometry-based metabolomics platform to evaluate global effects of simvastatin on intermediary metabolism. Analyses were conducted in 148 participants in the Cholesterol and Pharmacogenetics study who were profiled pre and six weeks post treatment with 40 mg/day simvastatin: 100 randomly selected from the full range of the LDL-C response distribution and 24 each from the top and bottom 10% of this distribution (“good” and “poor” responders, respectively). The metabolic signature of drug exposure in the full range of responders included essential amino acids, lauric acid (p<0.0055, q<0.055), and alpha-tocopherol (p<0.0003, q<0.017). Using the HumanCyc database and pathway enrichment analysis, we observed that the metabolites of drug exposure were enriched for the pathway class amino acid degradation (p<0.0032). Metabolites whose change correlated with LDL-C lowering response to simvastatin in the full range responders included cystine, urea cycle intermediates, and the dibasic amino acids ornithine, citrulline and lysine. These dibasic amino acids share plasma membrane transporters with arginine, the rate-limiting substrate for nitric oxide synthase (NOS), a critical mediator of cardiovascular health. Baseline metabolic profiles of the good and poor responders were analyzed by orthogonal partial least square discriminant analysis so as to determine the metabolites that best separated the two response groups and could be predictive of LDL-C response. Among these were xanthine, 2-hydroxyvaleric acid, succinic acid, stearic acid, and fructose. Together, the findings from this study indicate that clusters of metabolites involved in multiple pathways not directly connected with cholesterol metabolism may play a role in modulating the response to simvastatin treatment. Trial Registration ClinicalTrials.gov NCT00451828

References

[1]  Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, et al. (2004) Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 110: 227–239.
[2]  Jasinska M, Owczarek J, Orszulak-Michalak D (2007) Statins: a new insight into their mechanisms of action and consequent pleiotropic effects. Pharmacol Rep 59: 483–499.
[3]  Ridker PM (2009) The JUPITER trial: results, controversies, and implications for prevention. Circulation Cardiovascular quality and outcomes 2: 279–285.
[4]  Mangravite LM, Wilke RA, Zhang J, Krauss RM (2008) Pharmacogenomics of statin response. Curr Opin Mol Ther 10: 555–561.
[5]  Vaquero MP, Sanchez Muniz FJ, Jimenez Redondo S, Prats Olivan P, Higueras FJ, et al. (2010) Major diet-drug interactions affecting the kinetic characteristics and hypolipidaemic properties of statins. Nutr Hosp 25: 193–206.
[6]  Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, et al. (2008) Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 359: 2195–2207.
[7]  Bai JP (2010) Ongoing challenges in drug interaction safety: from exposure to pharmacogenomics. Drug Metab Pharmacokinet 25: 62–71.
[8]  Clayton TA, Baker D, Lindon JC, Everett JR, Nicholson JK (2009) Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism. Proc Natl Acad Sci U S A 106: 14728–14733.
[9]  Kaddurah-Daouk R, Baillie RA, Zhu H, Zeng ZB, Wiest MM, et al. (2011) Enteric microbiome metabolites correlate with response to simvastatin treatment. PLoS ONE 6: e25482.
[10]  Kaddurah-Daouk R, Kristal BS, Weinshilboum RM (2008) Metabolomics: a global biochemical approach to drug response and disease. Annu Rev Pharmacol Toxicol 48: 653–683.
[11]  Kaddurah-Daouk R, Krishnan KR (2009) Metabolomics: a global biochemical approach to the study of central nervous system diseases. Neuropsychopharmacology 34: 173–186.
[12]  Han X, Rozen S, Boyle SH, Hellegers C, Cheng H, et al. (2011) Metabolomics in early Alzheimer's disease: identification of altered plasma sphingolipidome using shotgun lipidomics. PLoS ONE 6: e21643.
[13]  Yao JK, Dougherty GG Jr, Reddy RD, Keshavan MS, Montrose DM, et al. (2010) Altered interactions of tryptophan metabolites in first-episode neuroleptic-naive patients with schizophrenia. Mol Psychiatry 15: 938–953.
[14]  Yao JK, Dougherty GG Jr, Reddy RD, Keshavan MS, Montrose DM, et al. (2010) Homeostatic imbalance of purine catabolism in first-episode neuroleptic-naive patients with schizophrenia. PLoS ONE 5: e9508.
[15]  Nicholson JK, Wilson ID, Lindon JC (2011) Pharmacometabonomics as an effector for personalized medicine. Pharmacogenomics 12: 103–111.
[16]  Wang TJ, Larson MG, Vasan RS, Cheng S, Rhee EP, et al. (2011) Metabolite profiles and the risk of developing diabetes. Nat Med 17: 448–453.
[17]  Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, et al. (2011) Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472: 57–63.
[18]  Ji Y, Hebbring S, Zhu H, Jenkins GD, Biernacka J, et al. (2011) Glycine and a glycine dehydrogenase (GLDC) SNP as citalopram/escitalopram response biomarkers in depression: pharmacometabolomics-informed pharmacogenomics. Clin Pharmacol Ther 89: 97–104.
[19]  Kaddurah-Daouk R, Baillie RA, Zhu H, Zeng ZB, Wiest MM, et al. (2010) Lipidomic analysis of variation in response to simvastatin in the Cholesterol and Pharmacogenetics Study. Metabolomics 6: 191–201.
[20]  Kaddurah-Daouk R, Boyle SH, Matson W, Sharma S, Matson S, et al. (2011) Pretreatment metabotype as a predictor of response to sertraline or placebo in depressed outpatients: a proof of concept. Transl Psychiatry 1: e26.
[21]  Simon JA, Lin F, Hulley SB, Blanche PJ, Waters D, et al. (2006) Phenotypic predictors of response to simvastatin therapy among African-Americans and Caucasians: the Cholesterol and Pharmacogenetics (CAP) Study. Am J Cardiol 97: 843–850.
[22]  Pal S, Thomson AM, Bottema CD, Roach PD (2003) Alpha-tocopherol modulates the low density lipoprotein receptor of human HepG2 cells. Nutr J 2: 3.
[23]  Rode S, Rubic T, Lorenz RL (2008) alpha-Tocopherol disturbs macrophage LXRalpha regulation of ABCA1/G1 and cholesterol handling. Biochem Biophys Res Commun 369: 868–872.
[24]  Devaraj S, Hugou I, Jialal I (2001) Alpha-tocopherol decreases CD36 expression in human monocyte-derived macrophages. J Lipid Res 42: 521–527.
[25]  Ricciarelli R, Zingg JM, Azzi A (2000) Vitamin E reduces the uptake of oxidized LDL by inhibiting CD36 scavenger receptor expression in cultured aortic smooth muscle cells. Circulation 102: 82–87.
[26]  Human JA, Ubbink JB, Jerling JJ, Delport R, Vermaak WJ, et al. (1997) The effect of Simvastatin on the plasma antioxidant concentrations in patients with hypercholesterolaemia. Clin Chim Acta 263: 67–77.
[27]  Vasankari T, Ahotupa M, Viikari J, Nuotio I, Strandberg T, et al. (2004) Effect of 12-month statin therapy on antioxidant potential of LDL and serum antioxidant vitamin concentrations. Ann Med 36: 618–622.
[28]  Neunteufl T, Kostner K, Katzenschlager R, Zehetgruber M, Maurer G, et al. (1998) Additional benefit of vitamin E supplementation to simvastatin therapy on vasoreactivity of the brachial artery of hypercholesterolemic men. J Am Coll Cardiol 32: 711–716.
[29]  Ryden M, Leanderson P, Kastbom KO, Jonasson L (2010) Effects of simvastatin on carotenoid status in plasma. Nutr Metab Cardiovasc Dis.
[30]  Piorunska-Stolzmann M, Piorunska-Mikolajczak A, Mikolajczyk Z (2003) Effect of simvastatin on trioleylglycerol hydrolysis and transacylation with cholesterol in serum of outpatients with coronary heart disease. Drugs Exp Clin Res 29: 37–43.
[31]  Baigent C, Landray M, Leaper C, Altmann P, Armitage J, et al. (2005) First United Kingdom Heart and Renal Protection (UK-HARP-I) study: biochemical efficacy and safety of simvastatin and safety of low-dose aspirin in chronic kidney disease. Am J Kidney Dis 45: 473–484.
[32]  Huskey J, Lindenfeld J, Cook T, Targher G, Kendrick J, et al. (2009) Effect of simvastatin on kidney function loss in patients with coronary heart disease: findings from the Scandinavian Simvastatin Survival Study (4S). Atherosclerosis 205: 202–206.
[33]  Namli S, Oflaz H, Turgut F, Alisir S, Tufan F, et al. (2007) Improvement of endothelial dysfunction with simvastatin in patients with autosomal dominant polycystic kidney disease. Ren Fail 29: 55–59.
[34]  Keshishian H, Addona T, Burgess M, Mani DR, Shi X, et al. (2009) Quantification of cardiovascular biomarkers in patient plasma by targeted mass spectrometry and stable isotope dilution. Mol Cell Proteomics 8: 2339–2349.
[35]  Laferrere B, Reilly D, Arias S, Swerdlow N, Gorroochurn P, et al. (2011) Differential metabolic impact of gastric bypass surgery versus dietary intervention in obese diabetic subjects despite identical weight loss. Sci Transl Med 3: 80re82.
[36]  Lee BE, Toledo AH, Anaya-Prado R, Roach RR, Toledo-Pereyra LH (2009) Allopurinol, xanthine oxidase, and cardiac ischemia. J Investig Med 57: 902–909.
[37]  Pacher P, Nivorozhkin A, Szabo C (2006) Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol Rev 58: 87–114.
[38]  Dawson J, Walters M (2006) Uric acid and xanthine oxidase: future therapeutic targets in the prevention of cardiovascular disease? Br J Clin Pharmacol.
[39]  Schwartz IF, Grupper A, Chernichovski T, Hillel O, Engel A, et al. (2011) Hyperuricemia attenuates aortic nitric oxide generation, through inhibition of arginine transport, in rats. J Vasc Res 48: 252–260.
[40]  Aura AM, Mattila I, Hyotylainen T, Gopalacharyulu P, Bounsaythip C, et al. (2011) Drug metabolome of the simvastatin formed by human intestinal microbiota in vitro. Mol Biosyst 7: 437–446.
[41]  Fiehn O, Wohlgemuth G, Scholz M, Kind T, Lee do Y, et al. (2008) Quality control for plant metabolomics: reporting MSI-compliant studies. Plant J 53: 691–704.
[42]  Fiehn O, Wohlgemuth G, Scholz M (2005) Setup and annotation of metabolomic experiments by integrating biological and mass spectrometric metadata. Proc Lect Notes Bioinformatics 3615: 224–239.
[43]  Scholz M, Fiehn O (2007) SetupX–a public study design database for metabolomic projects. Pac Symp Biocomput. pp. 169–180.
[44]  Storey JD, Tibshirani R (2003) Statistical significance for genomewide studies. Proceedings of the National Academy of Sciences of the United States of America 100: 9440–9445.
[45]  Stone EA, Ayroles JF (2009) Modulated modularity clustering as an exploratory tool for functional genomic inference. PLoS Genet 5: e1000479.
[46]  Trygg J, Wold S (2002) Orthogonal projections to latent structures (O-PLS). Journal of Chemometrics 16: 119–128.

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