High homocysteine induces betaine depletion

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Abstract

We demonstrated in the present study that betaine-homocysteine (Hcy) methyltransferase (BHMT) is a major pathway for Hcy removal in all situations of hyperhomocysteinaemia (HHcy). Hperhomocysteinaemia induces betaine depletion in plasma and tissues except in kidney, where betaine may play a crucial role as an osmolyte.

Abstract

Betaine is the substrate of the liver- and kidney-specific betaine-homocysteine (Hcy) methyltransferase (BHMT), an alternate pathway for Hcy remethylation. We hypothesized that BHMT is a major pathway for homocysteine removal in cases of hyperhomocysteinaemia (HHcy). Therefore, we measured betaine in plasma and tissues from patients and animal models of HHcy of genetic and acquired cause. Plasma was collected from patients presenting HHcy without any Hcy interfering treatment. Plasma and tissues were collected from rat models of HHcy induced by diet and from a mouse model of cystathionine β-synthase (CBS) deficiency. S-adenosyl-methionine (AdoMet), S-adenosyl-homocysteine (AdoHcy), methionine, betaine and dimethylglycine (DMG) were quantified by ESI—LC–MS/MS. mRNA expression was quantified using quantitative real-time (QRT)-PCR. For all patients with diverse causes of HHcy, plasma betaine concentrations were below the normal values of our laboratory. In the diet-induced HHcy rat model, betaine was decreased in all tissues analysed (liver, brain, heart). In the mouse CBS deficiency model, betaine was decreased in plasma, liver, heart and brain, but was conserved in kidney. Surprisingly, BHMT expression and activity was decreased in liver. However, in kidney, BHMT and SLC6A12 expression was increased in CBS-deficient mice. Chronic HHcy, irrespective of its cause, induces betaine depletion in plasma and tissues (liver, brain and heart), indicating a global decrease in the body betaine pool. In kidney, betaine concentrations were not affected, possibly due to overexpression of the betaine transporter SLC6A12 where betaine may be conserved because of its crucial role as an osmolyte.

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Homocysteine metabolism.

J Selhub (1999)

Homocysteine is a sulfur amino acid whose metabolism stands at the intersection of two pathways: remethylation to methionine, which requires folate and vitamin B12 (or betaine in an alternative reaction); and transsulfuration to cystathionine, which requires pyridoxal-5'-phosphate. The two pathways are coordinated by S-adenosylmethionine, which acts as an allosteric inhibitor of the methylenetetrahydrofolate reductase reaction and as an activator of cystathionine beta-synthase. Hyperhomocysteinemia, a condition that recent epidemiological studies have shown to be associated with increased risk of vascular disease, arises from disrupted homocysteine metabolism. Severe hyperhomocysteinemia is due to rare genetic defects resulting in deficiencies in cystathionine beta synthase, methylenetetrahydrofolate reductase, or in enzymes involved in methyl-B12 synthesis and homocysteine methylation. Mild hyperhomocysteinemia seen in fasting conditions is due to mild impairment in the methylation pathway (i.e. folate or B12 deficiencies or methylenetetrahydrofolate reductase thermolability). Post-methionine-load hyperhomocysteinemia may be due to heterozygous cystathionine beta-synthase defect or B6 deficiency. Early studies with nonphysiological high homocysteine levels showed a variety of deleterious effects on endothelial or smooth muscle cells in culture. More recent studies with human beings and animals with mild hyperhomocysteinemia provided encouraging results in the attempt to understand the mechanism that underlies this relationship between mild elevations of plasma homocysteine and vascular disease. The studies with animal models indicated the possibility that the effect of elevated homocysteine is multifactorial, affecting both the vascular wall structure and the blood coagulation system.

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The clinical significance of betaine, an osmolyte with a key role in methyl group metabolism.

Michael Lever, Sandy Slow (2010)

Betaine is an essential osmolyte and source of methyl groups and comes from either the diet or by the oxidation of choline. Its metabolism methylates homocysteine to methionine, also producing N,N-dimethylglycine. Betaine insufficiency is associated with the metabolic syndrome, lipid disorders and diabetes, and may have a role in vascular and other diseases. Betaine is important in development, from the pre-implantation embryo to infancy. Betaine supplementation improves animal and poultry health, but the effect of long-term supplementation on humans is not known, though reports that it improves athletic performance will stimulate further studies. Subsets of the population that may benefit from betaine supplementation could be identified by the laboratory, in particular those who excessively lose betaine through the urine. Plasma betaine is highly individual, in women typically 20-60 micromol/L and in men 25-75 micromol/L. Plasma dimethylglycine is typically <10 micromol/L. Urine betaine excretion is minimal, even following a large betaine dose. It is constant, highly individual and normally <35 mmol/mole creatinine. The preferred method of betaine measurement is by LC-MS/MS, which is rapid and capable of automation. Slower HPLC methods give comparable results. Proton NMR spectrometry is another option but caution is needed to avoid confusion with trimethylamine-N-oxide. 2010 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

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Biologic effects of nitrous oxide: a mechanistic and toxicologic review.

Mervyn Maze, Jörg Weimann, Robert Sanders (2008)

Nitrous oxide is the longest serving member of the anesthesiologist's pharmacologic armamentarium but remains a source of controversy because of fears over its adverse effects. Recently, the Evaluation of Nitrous oxide In a Gas Mixture for Anaesthesia (ENIGMA) trial reported that nitrous oxide use increases postoperative complications; further preclinical reports have suggested that nitrous oxide may contribute to neurocognitive dysfunction in the young and elderly. Therefore, nitrous oxide's longevity in anesthetic practice is under threat. In this article, the authors discuss the evidence for the putative toxicity of nitrous oxide, from either patient or occupational exposure, within the context of the mechanism of nitrous oxide's action. Although it would seem prudent to avoid nitrous oxide in certain vulnerable populations, current evidence in support of a more widespread prescription from clinical practice is unconvincing.

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Author and article information

Journal

Journal ID (nlm-ta): Biosci Rep

Journal ID (iso-abbrev): Biosci. Rep

Journal ID (hwp): ppbioscirep

Journal ID (publisher-id): BSR

Title: Bioscience Reports

Publisher: Portland Press Ltd.

ISSN (Print): 0144-8463

ISSN (Electronic): 1573-4935

Publication date (Electronic preprint): 28 April 2015

Publication date (Electronic): 7 July 2015

Publication date Collection: August 2015

Volume: 35

Issue: 4 ( displayID: 4 )

Electronic Location Identifier: e00222

Affiliations

[* ]Biochemistry Hormonology Laboratory, Robert-Debré Hospital, APHP, 48 Bd Serurier, Paris 75019, France

[† ]Paris Sud University, Pharmacy Faculty, 5 rue Jean Baptiste Clément, Chatenay-Malabry 92019, France

[‡ ]Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Lisbon 1649-003, Portugal

[§ ]Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, U.S.A.

[║ ]INSERM UMR 1141, Hôpital Robert Debré, 48 Bd Serurier, Paris 75019, France

[¶ ]Renal Unit, Department of Internal Medicine, AZ Sint-Jan AV, Bruges 8000, Belgium

[* ]*Reference Center for Inherited Metabolic Diseases, Robert-Debré Hospital, APHP, Paris 75019, France

[† ]†Faculté de Médecine Denis Diderot, Université Paris Diderot–Paris 7, Paris 75013, France

[‡ ]‡Laboratory for Clinical Biochemistry and Metabolism, Department of General Pediatrics, Center for Pediatrics and Adolescent Medicine University Hospital, Freiburg D-79106, Germany

Author notes

[ ¹ ]To whom correspondence should be addressed (email apolline.imbard@ 123456rdb.aphp.fr ).

Article

Publisher ID: e00222

DOI: 10.1042/BSR20150094

PMC ID: 4613678

PubMed ID: 26182429

SO-VID: 9c96e5db-f062-48d0-b52c-5af57e10efb7

License:

This is an open access article published by Portland Press Limited and distributed under the Creative Commons Attribution License 3.0.

History

Date received : 13 April 2015

Date revision received : 16 April 2015

Date accepted : 17 April 2015

Page count

Figures: 8, Tables: 2, References: 40, Pages: 13

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High homocysteine induces betaine depletion

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Network and Systems Medicine

Most cited references 33

Homocysteine metabolism.

The clinical significance of betaine, an osmolyte with a key role in methyl group metabolism.

Biologic effects of nitrous oxide: a mechanistic and toxicologic review.

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Cited by 7

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