Metabolomics reveals amino acids contribute to variation in response to simvastatin treatment.
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Trupp M, Zhu H, Wikoff WR, Baillie RA, Zeng ZB, Karp PD, Fiehn O, Krauss RM, Kaddurah-Daouk R
Metabolomics reveals amino acids contribute to variation in response to simvastatin treatment.
PLoS One. 2012;7(7):e38386. doi: 10.1371/journal.pone.0038386. Epub 2012 Jul 9.
- PubMed ID
- 22808006 [ View in PubMed]
- Abstract
UNLABELLED: 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.
DrugBank Data that Cites this Article
- Pharmaco-metabolomics
Drug Drug Groups Metabolite Change Description Simvastatin Approved A-tocopherol decreased Simvastatin decreases the level of A-tocopherol in the blood Simvastatin Approved Uridine decreased Simvastatin decreases the level of Uridine in the blood Simvastatin Approved Hydroxycarbamate decreased Simvastatin decreases the level of Hydroxycarbamate in the blood Simvastatin Approved Gamma-tocopherol decreased Simvastatin decreases the level of Gamma-tocopherol in the blood Simvastatin Approved Beta-alanine decreased Simvastatin decreases the level of Beta-alanine in the blood Simvastatin Approved Glycolic acid decreased Simvastatin decreases the level of Glycolic acid in the blood Simvastatin Approved Fructose decreased Simvastatin decreases the level of Fructose in the blood Simvastatin Approved Ethanolamine decreased Simvastatin decreases the level of Ethanolamine in the blood Simvastatin Approved 1-hexadecanol decreased Simvastatin decreases the level of 1-hexadecanol in the blood Simvastatin Approved Hydroxylamine decreased Simvastatin decreases the level of Hydroxylamine in the blood Simvastatin Approved Threonic acid decreased Simvastatin decreases the level of Threonic acid in the blood Simvastatin Approved Pseudo uridine decreased Simvastatin decreases the level of Pseudo uridine in the blood Simvastatin Approved Pelargonic acid decreased Simvastatin decreases the level of Pelargonic acid in the blood Simvastatin Approved Succinic acid decreased Simvastatin decreases the level of Succinic acid in the blood Simvastatin Approved Hexaric acid decreased Simvastatin decreases the level of Hexaric acid in the blood Simvastatin Approved Alpha-mannosylglycerate decreased Simvastatin decreases the level of Alpha-mannosylglycerate in the blood Simvastatin Approved Uric acid decreased Simvastatin decreases the level of Uric acid in the blood Simvastatin Approved 2-ketoisocaproic acid increased Simvastatin increases the level of 2-ketoisocaproic acid in the blood Simvastatin Approved Palmitoleic acid increased Simvastatin increases the level of Palmitoleic acid in the blood Simvastatin Approved Epsilon-caprolactam increased Simvastatin increases the level of Epsilon-caprolactam in the blood Simvastatin Approved 2-aminoadipic acid increased Simvastatin increases the level of 2-aminoadipic acid in the blood Simvastatin Approved LaUric acid decreased Simvastatin decreases the level of LaUric acid in the blood Simvastatin Approved Glycerol increased Simvastatin increases the level of Glycerol in the blood Simvastatin Approved 2-hydroxyvaleric acid decreased Simvastatin decreases the level of 2-hydroxyvaleric acid in the blood Simvastatin Approved Oxalic acid decreased Simvastatin decreases the level of Oxalic acid in the blood Simvastatin Approved Pentonic acid decreased Simvastatin decreases the level of Pentonic acid in the blood Simvastatin Approved Alpha-Aminoadipic acid increased Simvastatin increases the level of Alpha-Aminoadipic acid in the blood Simvastatin Approved Citrulline increased Simvastatin increases the level of Citrulline in the blood Simvastatin Approved Lysine increased Simvastatin increases the level of Lysine in the blood Simvastatin Approved Ornithine increased Simvastatin increases the level of Ornithine in the blood Simvastatin Approved Phenylalanine increased Simvastatin increases the level of Phenylalanine in the blood Simvastatin Approved Creatinine increased Simvastatin increases the level of Creatinine in the blood Simvastatin Approved Alanine increased Simvastatin increases the level of Alanine in the blood Simvastatin Approved Glucose decreased Simvastatin decreases the level of Glucose in the blood Simvastatin Approved Threonine increased Simvastatin increases the level of Threonine in the blood Simvastatin Approved Cholesterol decreased Simvastatin decreases the level of Cholesterol in the blood Simvastatin Approved Proline increased Simvastatin increases the level of Proline in the blood