全部 标题 作者
关键词 摘要

OALib Journal期刊
ISSN: 2333-9721
费用:99美元

查看量下载量

相关文章

更多...
PLOS ONE  2011 

Enteric Microbiome Metabolites Correlate with Response to Simvastatin Treatment

DOI: 10.1371/journal.pone.0025482

Full-Text   Cite this paper   Add to My Lib

Abstract:

Although statins are widely prescribed medications, there remains considerable variability in therapeutic response. Genetics can explain only part of this variability. Metabolomics is a global biochemical approach that provides powerful tools for mapping pathways implicated in disease and in response to treatment. Metabolomics captures net interactions between genome, microbiome and the environment. In this study, we used a targeted GC-MS metabolomics platform to measure a panel of metabolites within cholesterol synthesis, dietary sterol absorption, and bile acid formation to determine metabolite signatures that may predict variation in statin LDL-C lowering efficacy. Measurements were performed in two subsets of the total study population in the Cholesterol and Pharmacogenetics (CAP) study: Full Range of Response (FR), and Good and Poor Responders (GPR) were 100 individuals randomly selected from across the entire range of LDL-C responses in CAP. GPR were 48 individuals, 24 each from the top and bottom 10% of the LDL-C response distribution matched for body mass index, race, and gender. We identified three secondary, bacterial-derived bile acids that contribute to predicting the magnitude of statin-induced LDL-C lowering in good responders. Bile acids and statins share transporters in the liver and intestine; we observed that increased plasma concentration of simvastatin positively correlates with higher levels of several secondary bile acids. Genetic analysis of these subjects identified associations between levels of seven bile acids and a single nucleotide polymorphism (SNP), rs4149056, in the gene encoding the organic anion transporter SLCO1B1. These findings, along with recently published results that the gut microbiome plays an important role in cardiovascular disease, indicate that interactions between genome, gut microbiome and environmental influences should be considered in the study and management of cardiovascular disease. Metabolic profiles could provide valuable information about treatment outcomes and could contribute to a more personalized approach to therapy.

References

[1]  American Heart Association (2004) Heart Disease and Stroke Statistics - 2004 Update: American Heart Association.
[2]  Zhou Z, Rahme E, Pilote L (2006) Are statins created equal? Evidence from randomized trials of pravastatin, simvastatin, and atorvastatin for cardiovascular disease prevention. Am Heart J 151: 273–281.
[3]  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.
[4]  Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, et al. (2005) Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 366: 1267–1278.
[5]  Ridker PM (2009) The JUPITER trial: results, controversies, and implications for prevention. Circ Cardiovasc Qual Outcomes 2: 279–285.
[6]  Barber MJ, Mangravite LM, Hyde CL, Chasman DI, Smith JD, et al. (2010) Genome-wide association of lipid-lowering response to statins in combined study populations. PLoS ONE 5: e9763.
[7]  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.
[8]  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.
[9]  Kaddurah-Daouk R, Krishnan KR (2009) Metabolomics: a global biochemical approach to the study of central nervous system diseases. Neuropsychopharmacology 34: 173–186.
[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]  Mangravite LM, Wilke RA, Zhang J, Krauss RM (2008) Pharmacogenomics of statin response. Curr Opin Mol Ther 10: 555–561.
[12]  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.
[13]  Wikoff WR, Anfora AT, Liu J, Schultz PG, Lesley SA, et al. (2009) Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci U S A 106: 3698–3703.
[14]  Kinross JM, Darzi AW, Nicholson JK (2011) Gut microbiome-host interactions in health and disease. Genome Med 3: 14.
[15]  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.
[16]  Xiang X, Han Y, Neuvonen M, Pasanen MK, Kalliokoski A, et al. (2009) Effect of SLCO1B1 polymorphism on the plasma concentrations of bile acids and bile acid synthesis marker in humans. Pharmacogenet Genomics 19: 447–457.
[17]  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.
[18]  Houten SM, Watanabe M, Auwerx J (2006) Endocrine functions of bile acids. Embo J 25: 1419–1425.
[19]  Veiga P, Juste C, Lepercq P, Saunier K, Beguet F, et al. (2005) Correlation between faecal microbial community structure and cholesterol-to-coprostanol conversion in the human gut. FEMS Microbiol Lett 242: 81–86.
[20]  Lye HS, Rusul G, Liong MT (2010) Removal of cholesterol by lactobacilli via incorporation and conversion to coprostanol. J Dairy Sci 93: 1383–1392.
[21]  Deo AK, Bandiera SM (2008) Identification of human hepatic cytochrome p450 enzymes involved in the biotransformation of cholic and chenodeoxycholic acid. Drug Metab Dispos 36: 1983–1991.
[22]  Shitara Y, Sugiyama Y (2006) Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors: drug-drug interactions and interindividual differences in transporter and metabolic enzyme functions. Pharmacol Ther 112: 71–105.
[23]  Holtzman CW, Wiggins BS, Spinler SA (2006) Role of P-glycoprotein in statin drug interactions. Pharmacotherapy 26: 1601–1607.
[24]  Chen C, Mireles RJ, Campbell SD, Lin J, Mills JB, et al. (2005) Differential interaction of 3-hydroxy-3-methylglutaryl-coa reductase inhibitors with ABCB1, ABCC2, and OATP1B1. Drug Metab Dispos 33: 537–546.
[25]  Pasanen MK, Neuvonen M, Neuvonen PJ, Niemi M (2006) SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid. Pharmacogenet Genomics 16: 873–879.
[26]  Chen C, Lin J, Smolarek T, Tremaine L (2007) P-glycoprotein has differential effects on the disposition of statin acid and lactone forms in mdr1a/b knockout and wild-type mice. Drug Metab Dispos 35: 1725–1729.
[27]  Keskitalo JE, Kurkinen KJ, Neuvoneni PJ, Niemi M (2008) ABCB1 haplotypes differentially affect the pharmacokinetics of the acid and lactone forms of simvastatin and atorvastatin. Clin Pharmacol Ther 84: 457–461.
[28]  Klaassen CD, Aleksunes LM (2010) Xenobiotic, bile acid, and cholesterol transporters: function and regulation. Pharmacol Rev 62: 1–96.
[29]  Hsiang B, Zhu Y, Wang Z, Wu Y, Sasseville V, et al. (1999) A novel human hepatic organic anion transporting polypeptide (OATP2). Identification of a liver-specific human organic anion transporting polypeptide and identification of rat and human hydroxymethylglutaryl-CoA reductase inhibitor transporters. J Biol Chem 274: 37161–37168.
[30]  Gnerre C, Blattler S, Kaufmann MR, Looser R, Meyer UA (2004) Regulation of CYP3A4 by the bile acid receptor FXR: evidence for functional binding sites in the CYP3A4 gene. Pharmacogenetics 14: 635–645.
[31]  Rodrigues AC, Curi R, Genvigir FD, Hirata MH, Hirata RD (2009) The expression of efflux and uptake transporters are regulated by statins in Caco-2 and HepG2 cells. Acta Pharmacol Sin 30: 956–964.
[32]  Yamasaki D, Nakamura T, Okamura N, Kokudai M, Inui N, et al. (2009) Effects of acid and lactone forms of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on the induction of MDR1 expression and function in LS180 cells. Eur J Pharm Sci 37: 126–132.
[33]  Tazuma S, Kajiyama G, Mizuno T, Yamashita G, Miura H, et al. (1998) A combination therapy with simvastatin and ursodeoxycholic acid is more effective for cholesterol gallstone dissolution than is ursodeoxycholic acid monotherapy. J Clin Gastroenterol 26: 287–291.
[34]  Link E, Parish S, Armitage J, Bowman L, Heath S, et al. (2008) SLCO1B1 variants and statin-induced myopathy–a genomewide study. N Engl J Med 359: 789–799.
[35]  Lindon JC, Holmes E, Nicholson JK (2007) Metabonomics in pharmaceutical R&D. Febs J 274: 1140–1151.
[36]  Ridlon JM, Kang DJ, Hylemon PB (2006) Bile salt biotransformations by human intestinal bacteria. J Lipid Res 47: 241–259.
[37]  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.
[38]  Phillips KM, Ruggio DM, Bailey JA (1999) Precise quantitative determination of phytosterols, stanols, and cholesterol metabolites in human serum by capillary gas-liquid chromatography. J Chromatogr B Biomed Sci Appl 732: 17–29.
[39]  Tagliacozzi D, Mozzi AF, Casetta B, Bertucci P, Bernardini S, et al. (2003) Quantitative analysis of bile acids in human plasma by liquid chromatography-electrospray tandem mass spectrometry: a simple and rapid one-step method. Clin Chem Lab Med 41: 1633–1641.
[40]  Burkard I, von Eckardstein A, Rentsch KM (2005) Differentiated quantification of human bile acids in serum by high-performance liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 826: 147–159.
[41]  Zhao JJ, Xie IH, Yang AY, Roadcap BA, Rogers JD (2000) Quantitation of simvastatin and its beta-hydroxy acid in human plasma by liquid-liquid cartridge extraction and liquid chromatography/tandem mass spectrometry. J Mass Spectrom 35: 1133–1143.
[42]  Ayroles JF, Carbone MA, Stone EA, Jordan KW, Lyman RF, et al. (2009) Systems genetics of complex traits in Drosophila melanogaster. Nat Genet 41: 299–307.

Full-Text

Contact Us

service@oalib.com

QQ:3279437679

WhatsApp +8615387084133