Hypolipidaemic effects of fenofibrate are not altered by mildronate-mediated normalization of carnitine concentration in rat liver

Tsoko, Marcelline; Beauseigneur, Frédéric; Gresti, Joseph; Demarquoy, Jean; Clouet, Pierre

doi:10.1016/s0300-9084(00)88891-4

Cited by 11 publications

(12 citation statements)

References 22 publications

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“…3-Dehydrocarnitine and free carnitine showed an increased concentration in the blood of patients on fibrates. This agrees with previous findings that fenofibrate increases the level of carnitine [59, 60]. The fact that 3-dehydrocarnitine is an intermediate in the carnitine biosynthesis may explain the increase of the blood concentration of this metabolite.…”

Section: Discussionsupporting

confidence: 93%

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

et al. 2014

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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.

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Section: Discussionsupporting

confidence: 93%

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

et al. 2014

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“…The marked carnitine deficiency induced by mildronate in neonatal heart (70-80% reduction) observed in our experiment may have led to an impairment of lipid metabolism with a large increase of triglycerides and significant increase of CAT and CPT activities. In previous experiments heart and skeletal muscle appeared not to be greatly affected by mildronate-induced carnitine deficiency in adult rats (Spaniol et al, 2001;Tsoko et al, 1998). However, recent work (Zaugg et al, 2003) on carnitine-depleted adult rats demonstrated that mildronate treatment caused abnormalities in myocardial functions, including systolic dysfunction, reduced contractile reserve, and a blunted frequency-force relationship.…”

Section: Discussionmentioning

confidence: 90%

Carnitine depletion in rat pups from mothers given mildronate: A model of carnitine deficiency in late fetal and neonatal life

et al. 2005

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“…These data are indirectly supported by the fact that CLA feeding increases carnitine palmitoyltransferase activity in the liver of rats (44), which is usually observed in situations of impaired fatty acid oxidation (45).…”

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confidence: 70%

Conjugated linoleic acid isomers in mitochondria

Demizieux

Degrace

Gresti

et al. 2002

Journal of Lipid Research

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The beneficial effects exerted by low amounts of conjugated linoleic acids (CLA) suggest that CLA are maximally conserved and raise the question about their mitochondrial oxidizability. Cis -9, trans -11-C 18:2 (CLA1) and trans -10, cis -12-C 18:2 (CLA2) were compared to cis -9, cis -12-C 18:2 (linoleic acid; LA) and cis -9-C 16:1 (palmitoleic acid; PA), as substrates for total fatty acid (FA) oxidation and for the enzymatic steps required for the entry of FA into rat liver mitochondria. Oxygen consumption rate was lowest when CLA1 was used as a substrate with that on CLA2 being intermediate between it and the respiration on LA and PA. The order of the radiolabeled FA oxidation rate was PA ϾϾ LA Ͼ CLA2 Ͼ CLA1. Transesterification to acylcarnitines of the octadecadienoic acids were similar, while uptake across inner membranes of CLA1 and, to a lesser extent, of CLA2 was greater than that of LA or PA. Prior oxidation of CLA1 or CLA2 made re-isolated mitochondria much less capable of oxidising PA or LA under carnitine-dependent conditions, but without altering the carnitine-independent oxidation of octanoic acid. Therefore, the CLA studied appeared to be both poorly oxidizable and capable of interfering with the oxidation of usual FA at a step close to the beginning of the ␤ -oxidative cycle. -Demizieux, L., P. Degrace, J. Gresti, O. Loreau, J-P. Noël, J-M. Chardigny, J-L. Sébédio, and P. Clouet. Conjugated linoleic acid isomers in mitochondria: evidence for an alteration of fatty acid oxidation.

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Hypolipidaemic effects of fenofibrate are not altered by mildronate-mediated normalization of carnitine concentration in rat liver

Cited by 11 publications

References 22 publications

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

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

Carnitine depletion in rat pups from mothers given mildronate: A model of carnitine deficiency in late fetal and neonatal life

Conjugated linoleic acid isomers in mitochondria

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