Metabolomics approach reveals effects of antihypertensives and lipid-lowering drugs on the human metabolism.

Elisabeth Altmaier,Melanie Waldenberger,Gabi Kastenmüller,Gisela Fobo,Karsten Suhre,Christian Gieger,Barbara Thorand,Jerzy Adamski,Werner Römisch-Margl,Thomas Illig,Margit Heier,Christine Meisinger

doi:10.1007/s10654-014-9910-7

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s10654-014-9910-7) contains supplementary material, which is available to authorized users.

Highlights

Hypertension is a risk factor for the development of atherosclerosis and cardiovascular diseases as well as for renal failure
For each drug class—beta-blockers, angiotensin-I-converting enzyme (ACE) inhibitors, diuretics, statins and fibrates—we analyzed the metabolic dataset to identify metabolites whose blood serum levels significantly differ between subjects taking and not taking the respective drug (p value smaller than 3.39 9 10-5, the estimated significance level after correction for multiple testing—see ‘‘Statistical analysis’’)
For the group of ACE inhibitors we identified four metabolites that significantly associated with the intake of these drugs

Summary

Introduction

Hypertension is a risk factor for the development of atherosclerosis and cardiovascular diseases as well as for renal failure. Beta-blockers are a heterogeneous class of antihypertensive drugs Their main mode of action is the inhibition of noradrenaline and adrenaline b-adrenergic receptors, which diminishes the effect of the sympathetic nervous system on its target organ, especially on the smooth muscle tissue of the blood vessels and the heart. Most beta-blockers act on b1-, b2- and/or b3-adrenergic receptors, while some beta-blockers of the newer generation show an additional vasodilatory effect by, for example, blocking a1-adrenergic receptors [1,2,3]. Another important class of antihypertensive agents are angiotensin-I-converting enzyme (ACE) inhibitors. Diuretics inhibit the reabsorption of sodium in the renal tubules and their ability to alter long-term sodium balance induces important hemodynamic changes that result in a reduction in peripheral resistance and a decrease in blood pressure [5,6,7]

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Conclusion