PJMS- Volume 3 Number 1: January-June 2013

Review Article

Homocysteine: Is it the new cholesterol?

Gupta Madhur1

1
Professor and Head
Department of Biochemistry,
NKPSIMS & RC, Digdoh Hills,
Hingna, Nagpur-440019.
drmadhur20@rediffmail.com
Abstract:
Homocysteine (Hcy) an endogenous amino acid, containing a free thiol group, which in healthy cells is involved in
methionine and cysteine synthesis/resynthesis. Indirectly, Hcy participates in methyl, folate, and cellular thiol
metabolism. Elevated plasma homocysteine levels are a risk factor for Coronary Heart Disease (CHD).Though
numerous studies have demonstrated a high prevalence of hyperhomocysteinemia and CHD, yet
hyperhomocysteinemia has not been accepted yet as an established cardiovascular risk factor and remains
controversial. This review gives an insight into the possible role of hyperhomocysteinemia in the development of
cardiovascular disease. Thus treatment with vitamin B6 and B12 may be helpful in patients with
hyperhomocysteinemia to prevent the development of cardiovascular disease.
Keywords: Homocysteine, Cardiovascular disease (CHD).

Introduction :

Homocysteine (Hcy) is a homologue of the amino acid

cysteine and a non-protein amino acid which is not obtained
from the diet (1). It differs by an additional methylene bridge (-
CH2-). It is biosynthesized from methionine via a multi-step
process by the removal of its terminal C- methyl group.
Homocysteine can be recycled into methionine or converted
into cysteine with the aid of folic acid (also called folate) and
vitamins B6 and B12. First, methionine receives an adenosine
group from ATP, a reaction catalyzed by S-adenosyl-
methionine synthetase, to give S-adenosyl methionine (SAM).
SAM then transfers the methyl group to an acceptor molecule
(i.e. norepinephrine as an acceptor during epinephrine
synthesis, DNA methyl transferase as an intermediate
acceptor in the process of DNA methylation). The adenosine is
then hydrolyzed to yield L-homocysteine. L-Homocysteine has
two primary fates: conversion via tetrahydrofolate (THF) back
into L-methionine or conversion to L-cysteine (2).Thus the synthetase (CBS) mutation is thought to occur in 0.4% to 1.4%
metabolism stands at the intersection of two pathways: of the population. Homozygosity for the CBS mutation is quite
Remethylation to methionine, which requires folate and rare.
vitamin B12 (or betaine in an alternative reaction); and
transsulfuration to cystathionine, which requires pyridoxal-5'- The enzymes methylenetetrahydrofolate reductase
phosphate. The two pathways are coordinated by S-adenosyl (MTHFR), cystathionine beta-synthase (CBS) and methionine
methionine, which acts as an allosteric inhibitor of the synthase (MS) are associated with elevated levels of
methylenetetrahydrofolate reductase reaction and as an homocysteine. Genetic defects in genes encoding enzymes
activator of cystathionine beta-synthase. involved in homocysteine metabolism, or depletion of
important cofactors or (co)substrates for those enzymes,
The level of homocysteine in the blood varies with age, including folate, vitamin B12 and vitamin B6, may result in
gender, diet, hereditary factors and general health but it is elevated plasma homocysteine concentrations (3).
estimated that 5-10% of the population has homocysteine
levels that are considered high. The prevalence of Barring kidney malfunction, the occurrence of
hyperhomocysteinemia in the general population is not hyperhomocysteinemia indicates that homocysteine
known. Studies looking at the prevalence of homozygosity metabolism has in some way been disrupted and that the
(both (2) copies of the gene are mutated) for the thermolabile export mechanism is disposing into the blood excess
variant mutation in MTHFR (methylene tetrahydrofolate homocysteine that has accumulated in the cell. This prevents
reductase) have shown a prevalence near 15% in European, toxicity to the cell but leaves vascular tissue exposed to the
Middle Eastern and Japanese populations compared with a possibly deleterious effects of excess homocysteine. With the
range at or below 1.4% in African Americans. Patients who are exception of rare individuals who have congenital
heterozygous (1 copy of the mutated gene) are seen in 30-40% homocystinuria, people with high blood levels of
of the population. Heterozygosity for the cystathionine beta homocysteine do not have any obvious signs or symptoms.

2

Certain drugs like metformin (Glucophage), a drug to
modify insulin resistance; anti-epileptic drugs such as
phenobarbital, phenytoin (Dilantin), primidone (Mysoline)
and carbamazepine (Tegretol); levadopa (Sinemet) for
treatment of Parkinson's disease, methotrexate,
(Rheumatrex, Trexall) for treatment of cancer, psoriasis,
rheumatoid arthritis, and systemic lupus erythematosus,
androgen treatment nitrous oxide ("laughing gas"), a mild
anesthetic, lipid-lowering drugs such as fenofibrate (Tricor)
and bezafibrate (Bezalip) are suspected of increasing the level
of homocysteine in the blood.
Hyperhomocysteinemia has received increasing
attention during the past decade and has joined smoking,
dyslipidemia, hypertension, and obesity as an independent
risk factor for cardiovascular disease. An elevated plasma level
of homocysteine has long been known as an independent
predictor of cardiovascular disease (4,5). The small amount of
homocysteine normally found in the plasma is the result of a
cellular export mechanism that complements the catabolism
of homocysteine through transsulfuration by helping maintain
low intracellular concentrations of this potentially cytotoxic
sulfur amino acid (6,7).
It was way back that McCully (8) reported that a child
suffering from homocystinuria, cystathionuria, and
methylmalonic aciduria, secondary to an abnormality of
cobalamin metabolism, exhibited arterial lesions that were
strikingly similar to those seen in patients with cystathionine -
synthase deficiency. This observation led to the proposal that
the markedly elevated plasma homocysteine concentrations
found in persons with homocystinuria were responsible for
the development of premature occlusive vascular disease.
There is an ongoing debate regarding the association
linking the relationship as either a cause or effect between
homocysteine and cardiovascular disease. However, in the
absence of a clear mechanism linking homocysteine to
cardiovascular disease, an elevated level of plasma
homocysteine is an epiphenomenon, reflecting the presence
of some other proatherogenic factor that is actually
responsible for the cardiovascular disease. The possible link
may be a homocysteine-induced reduction in the
concentration of high density lipoproteins (HDLs).
Liao et al (9) and Mikael et al (10) have reported that
homocysteine reduces the concentration of HDL cholesterol in
plasma by inhibiting the hepatic synthesis of apoA-I, the main
HDL apolipoprotein. These studies thus support the inverse
correlation between the plasma concentrations of HDL
cholesterol and homocysteine (11,12) but also raise the real
possibility that a homocysteine-induced inhibition of apoA-I
synthesis is the mechanism linking homocysteine to the
development of atherosclerosis(13).Though the mechanism
by which homocysteine inhibits the synthesis of apoA-I is not
entirely clear theory has been postulated that homocysteine
3
PJMS- Volume 3 Number 1: January-June 2013
Review Article
reduces apoA-I protein synthesis in the liver without reducing
apoA-I mRNA (9). In addition, they found that homocysteine
reduced the rate of the plasma cholesterol esterification
catalyzed by the enzyme lecithin: cholesterol acyltransferase
and increased clearance of HDL cholesteryl esters from
plasma. Mikael et al (10) also found that homocysteine
reduces the synthesis of apoA-I, through the decrease in apoA-
I mRNA.Thus evidence suggests that homocysteine reduces
the plasma concentration of apoA-I and HDL cholesterol by
reducing the synthesis of apoA-I in the liver (14). Moreover, the
concentration of HDL cholesterol in human subjects correlates
inversely with the level of homocysteine in plasma. Hence low
concentration of HDL cholesterol may be a contributing factor
in patients with elevated levels of homocysteine increasing the
risk of developing cardiovascular disease.
Halil M et al (15) indicated that the increase in
homocysteine and other novel risk factors have been
associated with an increase in Framingham risk score in elderly
people. A meta-analysis in 1995 by Boushey et al (16)
suggested increase in Hcy concentrations was associated with
10% increase in CHD risk; and Clarke et al (17) demonstrated a
25% reduction in Hcy levels caused 11% decrease in the risk of
ischemic heart disease. It has also been suggested that tHcy is
an independent predictor of mortality in stable and acute
cardiovascular disease (18-20).
The prevailing view of the pathogenesis of coronary
heart disease involves a slow progression of coronary
atherosclerosis, followed by unstable angina, myocardial
infarction or sudden death. The acute event is frequently due
to rupture or erosion of an atherosclerotic plaque with
associated thrombus formation (21). There is increasing
evidence that homocysteine may affect the coagulation
system and the resistance of the endothelium to thrombosis
(22) and that it may interfere with the vasodilator and
antithrombotic functions of nitric oxide (23). Thus, the
vascular complications reported in patients with
homocystinuria are related to thrombosis rather than to
atherosclerosis (24-26).
The mechanism of action of Hcy biotoxicity may include:
1) Hcy-dependent oxidative stress and 2) Hcy-induced protein
structure modifications, named homocysteinylation.
Oxidative stress is generated during oxidation of the free thiol
group of Hcy, when Hcy binds via a disulphide bridge with
plasma proteins mainly albumin, or with other low-
molecular plasma thiols or with a second Hcy molecule.
Oxidation of Hcy may induce the subsequent oxidation of
proteins, lipids and nucleic acids (27).
Hcy and its derivatives are also known to induce free
radical formation and oxidative damage to the proteins (28).
Homocysteine mediated enhanced lipid peroxidation and
generation of free radicals such as superoxide anion, hydrogen
peroxide, hydroxyl, and thiol free radicals result in
PJMS- Volume 3 Number 1: January-June 2013
Review Article
inflammation could be related to the acute endothelial
dysfunction. The anti-atherothrombotic function of
endothelium derived nitric oxide is also reduced due to the
autooxidation of Hcy. Increased Hcy also stimulates the LDL
oxidase property which potentially promotes atherogenesis.
Thus homocysteine either by causing impairment of blood
flow and stimulation of the vascular smooth muscle
proliferation may be one of the signals for the inducing
apoptosis by activating an unfolded protein response(29).
Moderate hyperhomocysteinemia has been identified as a
new independent risk factor for cardiovascular disease (30).
Also, homocysteine is capable of increasing the activity of
HMG-CoA reductase, which results in increased cholesterol
synthesis (31).
Thus the contribution to the hemostatic abnormalities
by hyperhomocysteinemia is complex and unclear. The
thiolactone derivatives may play an important part in the
pathophysiology leading to cardiovascular disease.
Hyperhomocysteinemia disturbs hemostasis and shifts
the hemostatic mechanisms in favor of thrombosis. Normally
the fibrinolytic system comprises a proenzyme, plasminogen,
which can be converted to the active enzyme, plasmin, by
plasminogen activators. The main plasminogen activator in
the intravascular fibrinolysis is tissue plasminogen activator (t-
PA); another plasminogen activator-urokinase plasminogen
activator (u-PA) is mostly involved in the extracellular
proteolysis (32). Both u-PA and t-PA are serine proteinases that
act directly on the peptide bond Arg560-Val561 of the
plasminogen molecule, but the plasminogen activation
process induced by t-PA occurs on the fibrin clot surface. The
fibrinolytic activity of blood is regulated by specific inhibitors;
the inhibition of fibrinolysis takes place at the level of
plasminogen activation (by PA-inhibitors: plasminogen
activator inhibitor type-1, -2; PAI- 1 or PAI-2) or at the level of
plasmin activity (mainly by alpha 2-antiplasmin) (33).
The prothrombotic state observed in
hyperhomocysteinemia may arise not only due to
endothelium dysfunction or blood platelet and coagulation
activation, but also due to impaired fibrinolysis (34). Hcy-
modified fibrinogen is more resistant to the fibrinolytic action
(35-37). The other possible mechanism of the prothrombotic
effect of homocysteine may be the direct blockade of the t-PA
binding domain of annexin II, its major endothelial cell
receptor (38). t-PA attaches to endothelial cells via the
calcium-regulated phospholipid binding protein annexin II
and this interaction is inhibited by Hcy complexing with
Cysteine within annexin II putative hexapeptide binding
domain.
Homocysteine is also said to promote the release of
arachidonic acid, the formation of thromboxane A2 (39) and
the protein tyrosine phosphorylation in the blood platelets
(40,41). The blood platelets are more sensitive to agonists
4
including thrombin, epinephrine, vasopressin, serotonin, and
adenosine diphosphate, platelet aggregating factors,
thromboxane A2 and collagen or immune complexes (42). Hcy
or its thiolactone derivative also induces the hemostatic
proteins which may be the main cause for biotoxicity of Hcy in
cardiovascular disease. These react with the carbonyl groups
present in platelets and block protein degradation (43,44).
Thus homocysteine and homocysteine thiolactone increase
the platelet aggregation induced by thrombin (45). Hence Hcy
may act as a platelet agonist binding to fibronectin via a
disulphide linkage resulting in the functional change of
inhibition of fibrin binding to fibronectin (46).
Thus numerous factors play an important part in the
d e v e l o p m e n t o f c a r d i o va s c u l a r e v e n t s d u e t o
hyperhomocysteinemia. As treatment with vitamin B12 and
folic acid is extremely successful in the majority of the patients,
supplementation with these vitamins as options for lowering
homocysteine levels and decreasing risk for the development
of cardiovascular events can be taken into consideration.
Many antioxidants may reduce the toxic effects of
homocysteine or its derivatives in hemostatis. Dietary
supplements may give hope for decreasing
hyperhomocysteinemia and hence preventing thrombosis.
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