Brain Research 942 (2002) 46–50
S-adenosylmethionine is substrate for carrier mediated transport at the
blood–brain barrier in vitro
M. Chishty , A. Reichel , N.J. Abbott, D.J. Begley
Blood–Brain Barrier Research Unit
Neuroscience Research Centre
GKT School of Biomedical Sciences
s College London
Accepted 19 February 2002
S-adenosylmethionine (SAM) is the sole methyl donor in the CNS where it is involved in a multitude of biochemical reactions.
Peripherally administered SAM has been shown to increase SAM levels in cerebrospinal ﬂuid and is reported to be effective in the
treatment of numerous neurological disorders suggesting SAM crosses the blood–brain barrier (BBB). The mechanism of SAM entry into
the brain remains unknown, but the presence of adenosyl and methionine residues in the molecule suggests probable entry via carrier
mediated transport. We have investigated whether SAM utilises endogenous transport systems in cerebral endothelial cells, using RBE4
cells, an in vitro model of the BBB. SAM did not inﬂuence the transport of [ H]-methionine and only marginally reduced the uptake of
[ H]-leucine in RBE4 cells. The inhibition constant for the latter was 2.1160.29 mM (mean6S.E.M.). However, increasing
concentrations of SAM strongly inhibited the transport of [ H]-adenosine in RBE4 cells in both the presence and the absence of sodium in
the medium, with K values of 199632 and 13968.4 mM, respectively. Lineweaver-Burk plots suggest a competitive mode of inhibition.
The ﬁndings suggest that SAM is not recognised by the
-system transporter for large neutral amino acids at the brain endothelium. A
signiﬁcant interaction with the transport of adenosine, however, indicates that SAM has afﬁnity for the nucleoside carrier systems; this is
within the range of K values of natural substrates and suggest that SAM may enter the CNS via the Na -independent nucleoside carrier
systems at the brain capillary endothelium. 2002 Elsevier Science B.V. All rights reserved.
Neurotransmitters, modulators, transporters, and receptors
Uptake and transporters
Blood–brain barrier; Adomet; S-adenosylmethionine;
-System transporter; Nucleoside transport
1. Introduction pholipids and DNA as well as catecholamines and in-
S-adenosylmethionine (SAM) is formed following the SAM has been shown to reduce blood–brain barrier
adenosylation of methionine by the enzyme S- (BBB) breakdown and neuronal death following ischaemic
adenosylmethionine synthetase and performs a vital role in injury  and low CSF levels of SAM have been
numerous biochemical reactions in all living cells . In observed in several neuropsychiatric and neurological
the central nervous system (CNS), SAM plays an integral disorders including depression, brain ischaemia, Alzheim-
role in CNS metabolism as it is the sole methyl donor for er’s dementia and HIV-associated myelopathy .
several acceptor molecules including proteins, phos- Peripherally administered SAM has been found to be
effective in the treatment of several of these conditions,
with chronic parenteral and oral administration of SAM
Abbreviations: BBB, Blood–brain barrier; SAM, S-adeno-
resulting in increased CNS levels [2,20]. This indicates
that SAM readily reaches the brain parenchyma, sug-
Corresponding author. Tel.: 144-020-7848-6256; fax: 144-020-
gesting it penetrates the continuous layer of brain endo-
thelial cells lining the brain microvasculature constituting
firstname.lastname@example.org (M. Chishty).
the BBB. Although studies performed by Castagna et al.
Present address: Research Pharmacokinetics, Schering AG, Berlin,
 suggest that the blood-to-brain transfer of SAM in-
0006-8993/02/$ – see front matter 2002 Elsevier Science B.V. All rights reserved.