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Department of Human Nutrition and Dietetics, University of Illinois at Chicago, Chicago, IL 60612
1To whom correspondence should be addressed.
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OVERVIEW OF HOMOCYST(E)INE METABOLISM |
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 TOP OVERVIEW OF HOMOCYST(E)INE... RELATIONSHIP BETWEEN...MEDICAL IMPORTANCEPATHOPHYSIOLOGY OF...REFERENCES |
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Remethylation and transsulfuration are two major pathways of
homocysteine metabolism (Fig. 1
). In the liver, and occasionally in the kidney, the conversion of
homocysteine to methionine is catalyzed by
betaine-homocysteine methyltransferase. In all other tissues, this
conversion is catalyzed by 5-methyltetrahydrofolate-homocysteine
methyltransferase (methionine synthase) (Ueland and Refsum 1989
). Methionine synthase requires 5-methyltetrahydrofolate
(5-MTHF) as a methyl donor with methyl cobalamin serving as a cofactor.
5-MTHF is converted to tetrahydrofolate in this reaction; the methyl
group is used to remethylate cobalamin. These reactions involving
methionine synthase link homocysteine metabolism to folate and vitamin
B-12 metabolism (Ueland and Refsum 1989
).
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RELATIONSHIP BETWEEN HOMOCYSTEINE AND HOMOCYSTINE CONCENTRATIONS |
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TOPOVERVIEW OF HOMOCYST(E)INE...RELATIONSHIP BETWEEN...MEDICAL IMPORTANCEPATHOPHYSIOLOGY OF...REFERENCES |
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). The ratio that is maintained
between the free-reduced homocysteine and oxidized homocystine
suggests a tightly regulated system in the folate-adequate
individual, which keeps fasting plasma tHcy levels within a specific
and narrow range (<15 µmol/L is generally accepted). Intracellular homocysteine.
Manilow et al. (1994)
demonstrated in vitro that
homocyst(e)ine can be synthesized by erythrocytes and then transported
to the extracellular space. An in vitro study by Hultberg et al. (1998)
suggested that the intracellular free-reduced
homocysteine concentration in endothelial cells is influenced by the
extracellular concentration of homocyst(e)ine. If this is accurate,
then a mechanism is required for cells to regulate their
free-reduced homocysteine levels. Do they convert excess
homocyst(e)ine to methionine (via remethylation) or cysteine (via
transsulfuration) for export or does the intracellular concentration of
free-reduced homocysteine rise to maintain a balance with the
extracellular concentrations? If the intracellular levels increase, it
may be possible to identify which disease states are related to the
most significant elevations. This may be a more sensitive marker for
cardiovascular or metabolic disorders than is the plasma concentration
of tHcy. However, almost all research has focused on the total
concentration of various thiols in the plasma.
Extracellular homocysteine.
The question arises, what happens to plasma free-reduced homocysteine levels when tHcy levels are elevated? Do they rise in proportion to the increase in tHcy or does reduced homocysteine maintain its plasma levels of <3.0 µmol/L. If the levels of reduced homocysteine increase, either intracellularly or extracellularly, then it may be possible to also use reduced homocysteine levels in plasma as a more sensitive and meaningful indication of disease.
The redox thiol status theory suggests that reduced homocysteine acts
as a prooxidant, whereas reduced cysteine acts as an antioxidant
(Ueland et al. 1996
). Does this interplay between
cellular reduced cysteine and homocysteine affect plasma homocyst(e)ine
levels? If so, then plasma reduced homocysteine concentrations would
not be a sensitive indicator of disease because of simultaneous changes
that may occur in cysteine concentrations. Or does homocysteine
increase without an increase in cysteine, thereby reducing the
antioxidant protective actions of cysteine, leading to vascular
endothelial damage? The last step in the transsulfuration pathway of
homocysteine is catalyzed by cystathionine 
-lyase which cleaves
cystathionine, yielding free (reduced) cysteine, 
-ketobutyrate and
ammonia. Because cysteine is an allosteric inhibitor of this enzyme
(Yao 1975
), this could explain how high homocysteine
concentrations would not result in a commensurate elevation of
cysteine, thereby reducing the relative antioxidant effects of
cysteine.
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MEDICAL IMPORTANCE |
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TOPOVERVIEW OF HOMOCYST(E)INE...RELATIONSHIP BETWEEN...MEDICAL IMPORTANCEPATHOPHYSIOLOGY OF...REFERENCES |
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; Mansoor et al. 1993
). The high occurrence of
premature vascular disease in homocystinurics led to the formulation of
the homocyst(e)ine theory of arteriosclerosis (McCully 1969
).
Hyperhomocysteinemia, a disease involving abnormal homocysteine
metabolism, is characterized by plasma total homocyst(e)ine
concentrations ranging from 31 to 160 µmol/L (normal,
9–15 µmol/L). This disease can be the result of a dietary
folate deficiency or a cobalamin deficiency. Several studies have
concluded that moderate hyperhomocysteinemia is a powerful independent
risk factor for arteriosclerosis, similar in magnitude to
hypercholesterolemia, smoking and hypertension (Clarke et al. 1991
, Graham et al. 1997
). Treatment of moderate
hyperhomocysteinemia in otherwise healthy individuals with folic acid
appears to return the plasma homocyst(e)ine concentration to an
acceptable range and will slow the progression of cardiovascular
disease but will not reverse the vascular damage that was caused by
elevated plasma total homocyst(e)ine (Guttormsen et al. 1996
). Cystathionine ß-synthase–deficient individuals will
not benefit from this treatment; however, treatment with vitamin B-6
may reduce their plasma total homocyst(e)ine levels. A mutation that
reduces the basal activity of 5,10-methylenetetrahydrofolate reductase
(MTHFR) has been identified recently (Deloughery et al. 1996
). An association has been found between this mutation and
early-onset vascular disease; however, the MTHFR mutation is
not thought to be a genetic risk factor for late-onset
vascular disease (Deloughery et al. 1996
, Ma et al. 1996
). The importance of this mutation was discussed
recently by Bailey and Gregory (1999)
.
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PATHOPHYSIOLOGY OF HOMOCYST(E)INE-INDUCED VASCULAR DAMAGE |
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TOPOVERVIEW OF HOMOCYST(E)INE...RELATIONSHIP BETWEEN...MEDICAL IMPORTANCEPATHOPHYSIOLOGY OF...REFERENCES |
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). It has been hypothesized that homocyst(e)ine is
deleterious to endothelial cell function and may damage endothelial
cells that line the arteries. Endothelium regulates vascular tone and
permeability, the balance between coagulation and fibrinolysis, the
composition of the subendothelial matrix, the extravasation of
leukocytes and the proliferation of vascular smooth muscle cells
(De Jong et al. 1998
). Changes in one or more of these
properties may represent early manifestation of endothelium
dysfunction.
An animal model in minipigs with moderate, diet-induced
hyperhomocysteinemia shows that they develop "mega-artery syndrome"
with hyperpulsatile arteries, which is characterized by hypertension,
extended reactive hyperemia of conduit arteries and dilation of the
aorta (Rolland et al. 1995
). In their arterial tree,
major elastic lamina dislocations were observed, as well as hypertrophy
and reorientation of smooth muscle cells, showing that
hyperhomocysteinemia-induced vascular alterations favor the viscous
component of the wall rheology to the detriment of the elastic
component. This suggests that elevated homocyst(e)ine may facilitate
vascular smooth muscle cell proliferation.
Bellamy et al. (1998)
assessed endothelium function in
healthy humans before and after an oral methionine load. After the
methionine load (100 mg/kg), plasma total homocyst(e)ine increased from
7.9 µmol/L (baseline) to 23.1 µmol/L (4 h).
This was associated with a decrease in flow-mediated brachial
artery dilation from 0.12 mm to 0.06 mm, despite similar hyperemic
blood flow (67 mL/min vs. 78 mL/min). Flow-mediated brachial artery
dilation reflects endothelium-dependent vasodilation. It can be
largely blocked by inhibitors of nitric oxide synthase and is therefore
attributable predominantly to nitric oxide activity (Bellamy et al. 1998
). The time course of the impairment of
flow-mediated vasodilation mirrored the time course of the increase
in homocyst(e)ine concentration, which is consistent with a direct
toxic effect of homocyst(e)ine.
Hyperhomocysteinemic animals and humans have recently been found to
have endothelium that is unable to produce adequate amounts of
endothelium-derived relaxing factor (nitric oxide) (Lentz et al. 1996
). These investigators used a modified diet that was
enriched in methionine (1.0 g/100 g), relatively depleted in folic acid
(0.15 mg/100 g) and free of choline to induce moderate
hyperhomocysteinemia in adult cynomolgus monkeys. They found that the
blood vessels exhibited increased platelet-mediated
vasoconstriction, impaired endothelium-dependent vasodilation and
decreased thrombomodulin-dependent activation of protein C as a
consequence of altered vascular function in the absence of structural
vascular disease. De Jong et al. (1997)
studied 123
clinically healthy siblings of young vascular patients with mild
hyperhomocysteinemia. Flow mediated, endothelium-dependent
vasodilation in the brachial artery correlated inversely with the
postmethionine load increases in the plasma homocyst(e)ine level, but
not with the fasting level of homocyst(e)ine. This might indicate some
problem with remethylation/transsulfuration that is triggered by
elevated methionine or a reduced ability to metabolize excess
homocyst(e)ine. From the above observations, the disturbance in the
endothelium-dependent vasodilation may well be caused by a
decreased production and/or action of nitric oxide.
Homocysteine is readily oxidized when added to plasma, leading to the
formation of homocystine, homocysteine-mixed disulfides and
homocysteine thiolactone. During the oxidation of the sulfhydryl group,
the superoxide anion radical and hydrogen peroxide are generated. These
radicals can initiate lipid peroxidation at the endothelial cell
surface as well as within lipoprotein particles in plasma
(Loscalzo 1996
). Sulfhydryl compound autoxidation is
thought to attenuate endothelial concentrations of nitric oxide through
the reaction of nitric oxide with the radicals generated during
sulfhydryl autoxidation (Loscalzo 1996
). In addition,
homocyst(e)ine can inhibit the synthesis and production of glutathione
peroxidase, which detoxifies hydrogen peroxide and lipid peroxides.
Mild increases in plasma homocyst(e)ine levels (>16
µmol/L) have been associated with the presence of vascular
disease especially of coronary, iliac, femoral and carotid arteries
(Fortin and Genest 1995
). Elevated homocyst(e)ine
concentrations may alter the prothrombolytic and anticoagulant
activities of vascular cells. Rodgers and Cohn (1990)
showed that elevated levels of homocyst(e)ine decrease protein C
activation by decreasing the activity of thrombomodulin. Homocyst(e)ine
has also been shown to increase the activity of tissue factor in
endothelial cells, to reduce tissue plasminogen activator binding to
its endothelial cell receptor, annexin II, and to enhance the activity
of coagulation factor V in endothelial cells (Fortin and Genest 1995
). The reduced binding to annexin II can facilitate the
generation of thrombin, which promotes smooth muscle cell proliferation
(Hajjer 1993
). Harpel et al. (1992)
found
that homocysteine increases the affinity of lipoprotein (a) [Lp(a)]
for fibrin. Lp(a) is structurally homologous to plasminogen and
can interfere with fibrinolysis by competing with plasminogen for
binding sites on cells and molecules, including fibrin (Harpel et al. 1992
). These observations suggest that elevated
homocyst(e)ine may be atherogenic by inducing a procoagulatory state.
The pathogenesis of homocyst(e)ine-induced cardiovascular disease has not been identified definitively. Homocysteine, in its reduced state, inhibits nitric oxide synthase, leading to a decrease in the relaxation of blood vessels. This altered vasodilation, not constriction, may increase blood pressure and lead to physical damage to the endothelial cells. This damage may then provide an opportunity for other homocyst(e)ine-related mechanisms (smooth muscle cell proliferation; impaired flow-mediated, endothelium-dependent vasodilation; lipid peroxidation and inhibition of glutathione peroxidase production; and increased generation of thrombin) to further damage the endothelium. This damage to the endothelium may then manifest itself in the form of vascular disease. The insidious nature of plasma homocysteine requires increased research efforts to confirm or invalidate this process. If validated, dietary intervention, in the form of a diet that is lower in animal-based foods or increased vitamin intake may reduce the occurrence and severity of cardiovascular disease. Although a low fat, low cholesterol diet is widely recommended for many patients with cardiovascular disease, the current justifications supporting this diet may be inaccurate. Homocyst(e)ine-induced vascular damage may be the major dietary connection to cardiovascular disease, not a diet high in cholesterol and saturated fat.
In conclusion, intracellular homocysteine is the metabolically active
form because homocystine is not converted to either methionine or
cystathionine. This highly reactive nature of the reduced homocysteine
fraction makes it a good candidate for further study. The intracellular
compartment maintains its homeostasis by exporting excess homocysteine
to the extracellular space. Thus, intracellular homocysteine appears to
be responsible for the transient increase that occurs in the plasma
total homocyst(e)ine. This "spill-over" mechanism allows cells to
maintain a fairly constant concentration of homocysteine. When the
intracellular metabolism of homocysteine is diminished, either from
inadequate vitamin intake or excessive substrate intake, cells quickly
reach a critical concentration of homocysteine, and a rise in plasma
homocyst(e)ine values follows. For these reasons, we recommend that
special attention should be paid in future studies to intracellular and
extracellular free-reduced homocysteine concentrations, in addition
to determination of total homocyst(e)ine concentrations in the plasma.
Methods that can trap and separate the free-reduced homocysteine
have been described (Mansoor et al. 1992
). Additional
minor alterations in current protocols should allow for detailed
examination of free-reduced homocysteine metabolism. Although the
critical concentration for intracellular homocysteine is not yet known,
its identification can then permit the development of interventions to
minimize the many adverse cellular and biochemical events triggered by
elevated intracellular homocysteine.
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FOOTNOTES |
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Manuscript received April 16, 1999. Initial review completed April 27, 1999. Revision accepted June 24, 1999.
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REFERENCES |
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-cystathionase. Abbreviations: THF,
tetrahydrofolate; PLP, pyridoxal (PL) 5'-phosphate; ATP, adenosine
5'-triphosphate; B-12, vitamin B-12; SAM, S-adenosyl-methionine.
[Reproduced with permission from Selhub and Miller (1992)