An Overview of Homocysteine Metabolism - Homocysteine in Protein Structure/Function and Human Disease - page 17

2.2.7 Cystathionine

There is no indication that cystathionine is toxic [20]. Although it accumulates
under pathological conditions, such as cystathionase deficiency or cancer,
cystathionine seems to be benign. However, the lack of cystathionine synthesis
has been shown to be responsible for liver steatosis and kidney injury in mouse
models [181].

2.2.8 Homocysteic Acid

HCA is an analog of the neurotransmitter glutamate. Because of this, HCA is a
selective agonist of glutamate receptors [182]. In tissue cultures, supplementation
with HCA is toxic to human [183] and animal [184] neuronal cells.
Elevation of HCA from undetectable levels to 119 M that occurs in

cerebrospinal fluid of children after methotrexate treatment is associated with
neurological toxicity [119]. Persistent cognitive deficits in rats are induced by
intrathecal methotrexate treatment and are associated with elevated concentrations
of HCA (and HSA) in the cerebrospinal fluid [123]. These deficits are reversed by
intraperitoneal injections of dextromethorphan, a noncompetitive antagonist of the
N-methyl- D -aspartate receptor (NMDA). These findings are consistent with a
known agonist role of HCA at glutamate receptors. Overstimulation of the
NMDA receptor by HCA has been suggested to contribute to the central nervous
system pathology observed in patients with homocystinuria [185]. Consistent with
this suggestion, HCA is present in homocystinuric patients (at ~7

20 μ

M in plasma
[186] and in urine [120]). However, it is not known whether HCA accumulates in
CNS of these patients.

μ