Homocysteine is transported by the microvillous plasma membrane of human placenta

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.

Fig. 1

Homocysteine metabolic pathways. Homocysteine can be metabolised by three metabolic pathways in tissues. (1) Remethylation to methionine using 5-methyltetrahydrofolate (5-MTHF) as methyl donor, catalysed by the vitamin B₁₂-dependent action of methionine synthase (MS). THF is then re-cycled to form 5-MTHF, catalysed by 5,10-methylene tetrahydrofolate reductase (MTHFR). Methionine then acts as the precursor for the ATP-dependent synthesis of the primary methyl donor S-adenosylmethionine (SAM) which is involved in various methylation reactions, producing homocysteine and methylated acceptor(s). (2) Betaine can be utilized as an alternative methyl donor to generate methionine and dimethylglycine (DMG), catalysed by betaine-homocysteine methyltransferase (BHMT). (3) Homocysteine can enter the transsulphuration pathway being converted to cysteine through the action of cystathionine β-synthase (CβS)

Fig. 2

The exchange barrier of human placenta. Electron micrograph showing the two cellular layers involved in transplacental exchange: the transporting epithelium of the syncytiotrophoblast and fetal capillary endothelium. The syncytiotrophoblast has two plasma membranes, a maternal-facing microvillous plasma membrane which is in direct contact with maternal blood in the intervillous space and a basal plasma membrane which faces the fetal capillary containing fetal blood. Image kindly supplied by Dr Carolyn Jones

Fig. 3

Maternofetal transfer of homocysteine. Schematic representation of the involvement of transport mechanisms systems L, A and y⁺L in the maternofetal transfer of Hcy across the human placenta. The scheme includes the possibility that as yet uncharacterised mechanisms may also be involved, denoted as carrier ‘?’. AA Amino acid