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Homocysteine is transported by the microvillous plasma membrane of human placenta

  • Homocysteine and B-Vitamin Metabolism
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Elevated maternal plasma concentrations of homocysteine (Hcy) are associated with pregnancy complications and adverse neonatal outcomes. The postulate that we wish to advance here is that placental transport of Hcy, by competing with endogenous amino acids for transporter activity, may account for some of the damaging impacts of Hcy on placental metabolism and function as well as fetal development. In this article, we provide an overview of some recent studies characterising the transport mechanisms for Hcy across the microvillous plasma membrane (MVM) of the syncytiotrophoblast, the transporting epithelium of human placenta. Three Hcy transport systems have been identified, systems L, A and y+L. This was accomplished using a strategy of competitive inhibition to investigate the effects of Hcy on the uptake of well-characterised radiolabelled substrates for each transport system into isolated MVM vesicles. The reverse experiments were also performed, examining the effects of model substrates on [35S]L-Hcy uptake. This article describes the evidence for systems L, A and y+L involvement in placental Hcy transport and discusses the physiological implications of these findings with respect to placental function and fetal development.

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Abbreviations

BCH:

2-aminobicyclo[2.2.1]heptane-2-carboxylic acid

BM:

Basal plasma membrane

FGR:

Fetal growth restriction

Hcy:

Homocysteine

HHcy:

Hyperhomocysteinemia

MeAIB:

α-(methylamino)isobutyric acid

MVM:

Microvillous plasma membrane

SNAT:

Sodium-coupled neutral amino acid transporter

tHcy:

Total Hcy

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Acknowledgements

The work described in this article was supported by the Medical Research Council (MRC) (G0500647; J.D.G., S.W.D’S., C.P.S.) and a MRC Doctoral Training Studentship (E.T.). This work was also supported by Grant HL52234 from the National Heart, Lung and Blood Institute of the National Institutes of Health (D.W.J.). The Maternal and Fetal Health Research Group is supported by the Manchester NIHR Biomedical Research Centre. We would like to acknowledge that Professor Jonathan Clayden and Mr Lee Mullen (Department of Chemistry, University of Manchester) synthesised the L-Hcy used in our studies, and we extend our grateful thanks to them. We are also grateful to Dr Carolyn Jones for providing the electron micrograph of the placental barrier.

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Authors and Affiliations

  1. Maternal and Fetal Health Research Group, School of Biomedicine, University of Manchester, Manchester Academic Health Science Centre, St Mary’s Hospital, Oxford Road, Manchester, M13 9WL, UK

    Eleni Tsitsiou, Colin P. Sibley, Stephen W. D’Souza & Jocelyn D. Glazier

  2. Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

    Otilia Catanescu & Donald W. Jacobsen

  3. Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, USA

    Donald W. Jacobsen

Authors
  1. Eleni Tsitsiou
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  2. Colin P. Sibley
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  3. Stephen W. D’Souza
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  4. Otilia Catanescu
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  5. Donald W. Jacobsen
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  6. Jocelyn D. Glazier
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Corresponding author

Correspondence to Jocelyn D. Glazier.

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Communicated by: Henk Blom

Competing interest: None declared.

Conflict of interests: None to declare.

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Tsitsiou, E., Sibley, C.P., D’Souza, S.W. et al. Homocysteine is transported by the microvillous plasma membrane of human placenta. J Inherit Metab Dis 34, 57–65 (2011). https://doi.org/10.1007/s10545-010-9141-3

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