title: Metabolomics approach reveals effects of antihypertensives and lipid-lowering drugs on the human metabolism.
abstract: The mechanism of antihypertensive and lipid-lowering drugs on the human organism is still not fully understood. New insights on the drugs' action can be provided by a metabolomics-driven approach, which offers a detailed view of the physiological state of an organism. Here, we report a metabolome-wide association study with 295 metabolites in human serum from 1,762 participants of the KORA F4 (Cooperative Health Research in the Region of Augsburg) study population. Our intent was to find variations of metabolite concentrations related to the intake of various drug classes and--based on the associations found--to generate new hypotheses about on-target as well as off-target effects of these drugs. In total, we found 41 significant associations for the drug classes investigated: For beta-blockers (11 associations), angiotensin-converting enzyme (ACE) inhibitors (four assoc.), diuretics (seven assoc.), statins (ten assoc.), and fibrates (nine assoc.) the top hits were pyroglutamine, phenylalanylphenylalanine, pseudouridine, 1-arachidonoylglycerophosphocholine, and 2-hydroxyisobutyrate, respectively. For beta-blockers we observed significant associations with metabolite concentrations that are indicative of drug side-effects, such as increased serotonin and decreased free fatty acid levels. Intake of ACE inhibitors and statins associated with metabolites that provide insight into the action of the drug itself on its target, such as an association of ACE inhibitors with des-Arg(9)-bradykinin and aspartylphenylalanine, a substrate and a product of the drug-inhibited ACE. The intake of statins which reduce blood cholesterol levels, resulted in changes in the concentration of metabolites of the biosynthesis as well as of the degradation of cholesterol. Fibrates showed the strongest association with 2-hydroxyisobutyrate which might be a breakdown product of fenofibrate and, thus, a possible marker for the degradation of this drug in the human organism. The analysis of diuretics showed a heterogeneous picture that is difficult to interpret. Taken together, our results provide a basis for a deeper functional understanding of the action and side-effects of antihypertensive and lipid-lowering drugs in the general population.
authors.affiliation: Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany, elisabeth.altmaier@helmholtz-muenchen.de.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Altmaier
authors.forename: Gisela
authors.initials: G
authors.lastname: Fobo
authors.forename: Margit
authors.initials: M
authors.lastname: Heier
authors.forename: Barbara
authors.initials: B
authors.lastname: Thorand
authors.forename: Christine
authors.initials: C
authors.lastname: Meisinger
authors.forename: Werner
authors.initials: W
authors.lastname: Römisch-Margl
authors.forename: Melanie
authors.initials: M
authors.lastname: Waldenberger
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.forename: Jerzy
authors.initials: J
authors.lastname: Adamski
authors.forename: Karsten
authors.initials: K
authors.lastname: Suhre
authors.forename: Gabi
authors.initials: G
authors.lastname: Kastenmüller
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000009:adverse effects; D000368:Aged; D000369:Aged, 80 and over; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D050260:Carbohydrate Metabolism / Q000187:drug effects; D004232:Diuretics / Q000009:adverse effects; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects; D006949:Hyperlipidemias / Q000188:drug therapy* / Q000378:metabolism; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D055432:Metabolomics; D008875:Middle Aged
chemical_list: D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D004232:Diuretics; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents