Article Type : Review Article
Authors : Lissoni P, Di Fede G and Messina G
Keywords : Homocysteine; Melatonin; Methionine; Pineal gland; Systemic diseases
Is it possible to identify a biological alterations
occurring in the overall systemic human diseases? Generally, most biomarkers
are in relation to only a few number of similar pathologies, whereas two main
alterations have been described in the most important human pathologies,
including hypertension, brain and cardiac ischemic disorders, tumors, and neuropsychiatric
diseases, consisting of an enhanced production of homocysteine (HCY) and a
diminished nocturnal production of the pineal hormone melatonin (MLT). However,
these two alterations would be characterized by opposite biological effects,
since MLT has been proven to protect cardiovascular and nervous functions,
whereas HCY and its metabolites may be toxic for several tissues, by
predisposing to metabolic, nervous, and cardiovascular diseases. Therefore, the
question to be solved is to establish which relation may exist between
hyper-production of HCY and diminished secretion of MLT. According to the
results available in the literature, since it has been shown that MLT may
counteract HCY production and activity, it is possible to conclude that the
primary alteration is consisting of an age-dependent diminished pineal
function, whereas the enhanced HCY production would simply represent the
consequence of the diminished pineal endocrine activity.
Each human local or
systemic disease is characterized by alterations involving some clinical
parameters, which, however, may represent the specific cause of disease, or the
simple consequential effect of the pathogenesis of disease. In some cases, it
is easy to distinguish the cause of disease from its effects, as occurring in
the diabetes, whose consequence is consisting of the increase in glucose blood
levels, but whose cause is the diminished insulin production, or an enhanced
insulin resistance. On the contrary, in some other cases, it is more difficult
to clinically distinguish the cause of disease from its effects by the simple
laboratory analyses. This is the case of the evidence of hyper-homocysteinemia
in most human systemic diseases, consisting of the presence of abnormally high
blood levels of homocysteine (HCY) [1-5]. At present, however, despite the
evidence of an association between increase blood concentrations of HCY with
several human systemic diseases [1-5], it remains to be established whether the
increased levels of HCY may represent the causative factor, or the simple
effect of other biological alterations, as confirmed by the fact that the
correction of the hyper-homocysteinemia does not allow a concomitant reduction
in the incidence of hyper-homocysteinemia supposed related-pathologies [6].
From a physiopathological point of view, the great number of biomarkers could
be sub-divided into three main subtypes, represented by disease-specific
markers, biological response markers, and disease mechanism-related markers.
Most biomarkers regard single specific diseases, or a few number of similar
diseases. Biological response markers include several systemic diseases, but
they simply reflect the effects of the systemic pathology, as in the case of
the inflammatory status, which may be clinically documented by several
marekers, including CRP, ESR, neopterin, and soluble IL-2 receptors [7]. On the
contrary, some other biomarkers also provided by a general significance are ill
relation not only to the effects of some diseases, but the mechanisms
responsible for the cause of disease itself. According to the great number of
opinions or hypotheses reported in the literature, it is possible to identify
two main altered clinical parameters, which have been proposed as the cause of
most human systemic pathologies, consisting of the enhanced production of HCY
with a following condition of hyper-homo-cysteinemia [1-5], and the diminished
production of the pineal indole hormone melatonin (MLT), particularly during
the night, with a consequent loss of its physiological light/dark circadian
rhythm [8]. These different conditions could represent two independent
pathogenetic factors, or alternatively they could be connected by a
cause/effect ratio, but in this case it would have to be established which is
the cause, and which is the effect. To solve this question, obviously firstly
we have to analyze which is in details the biological activities of both HCY
and MLT, in any case by constantly taking into consideration their opposite
effects, since while MLT has been proven to protect against most human systemic
pathologies [8-10], HCY would promote their development [1-5], with two
consequent opposite therapeutic strategies, consisting of enhancing MLT blood
levels and decreasing those of HCY.
HCY is a sulfur
containing aminoacid, which is produced during the metabolism of the aminoacid
methionine (MT) to cysteine (CYS). MET is the unique source of HCY, which may
undergo three different metabolic pathways, to reform MET, to be metabolized to
CYS, or to be cyclized to form homocysteinethiolactone (HTL), which would
constitute the main toxic intermediate of HCY [11]. The increase in HCY blood
concentrations, which are generally less than 12 micromol/L, may be induced by
several causes, including a defective metabolism of MET due to gene mutations,
vitamins deficiencies, namely those of folic acid, B6 and B12, high consumption
of meat, and deficiency of cystathionine-beta synthase, which is involved in
the production of hydrogen sulfide (H2S), a lipid-soluble gaseous molecule
[12], and which has been proven to play a hypotensive action, to promote brain
development, and to decrease the neuronal excitability. A diminished endothelial
production of H2S would play a role in the pathogenesis of the hypertension.
Moreover, the toxicity related to a condition of hyper-homocysteinemia would
depend at least in part on the concomitant presence of a demised H2S endogenous
production [12]. HCY has appeared to stimulate the endothelial production of
inflammatory cytokines, as well as the expression of some vascular cell
adhesion molecules, with a following increased monocyte adhesion to the
arterial endothelium, which may contribute to the development of the
atherosclerotic processes by facilitating the monocyte-macrophage infiltration
into the arterial wall [12]. Moreover, HCY may induce tissue damage by causing
an oxidative stress leading to oxidation of low density lipoproteins (LDL), which
also contribute to the atherosclerotic pathogenesis. Finally, an altered HCY
metabolism may allow the production of S-nitroso-homocysteine, which induces
endothelial dysfunction and inhibition of the vasodilatory action of nitric
oxide (NO).
Hyper-cysteinemia has
been proven to be an independent risk factor for atherosclerosis [1], cardiac
and brain ischemic disorders [1], neurodegenerative pathologies [2], neoplasms
[3], osteoporosis [4], and insuline resistance [5]. HCY may predispose to the
neurodegenerative diseases by enhancing the oxidative stress [2,11], and to
osteoporosis by stimulating the osteoclastic activity [4]. On the contrary, the
relation between HCY production and tumor development is more complex, since it
has been shown that proliferating tumor cells may produce and release HCY [3].
Then, cancer-related hyper-homocysteinemia would constitute a marker of tumor
growth, biological malignancy, and extension, rather than a causative factor
for tumor onset [3]. The hyper-homocysteinemia may be treated by
supplementation with folic acid, B12 and B6 vitamins [6,11], but the control of
hyper-homocysteinemia does not guarantee the control of
hyper-homocysteinemia-related pathology.
The pineal gland is a
neuroendocrine organ, which acts as a neurochemical transducer, by representing
the only structure of human body able to modulate the whole biological systems
in relation to the universal energetic conditions, namely the light/dark rhythm
[8], through the circadian secretion of several indole and beta-carboline
hormones, the most known of them is MLT. The light inhibits, whereas the dark
stimulates MLT secretion from the pineal gland. Then, the evidence of a normal
light/dark rhythm of MLT secretion, with higher levels during the night and
lower concentrations during the day, would constitute a fundamental clinical
parameter of the status of health. The main stimulus for MLT secretion is
represented by beta-adrenergic receptor agonists [8], but MLT release is also
stimulated by alpha-1 agonists, alpha-2 antagonists [8], mu-opioid agonists
[13], cannabinoid agents [14], oxytocin [15], and the cardiac hormone atrial
natriuretic peptide (ANP) [16], whereas it is inhibited by beta-blockers and
alpha-2 agonists [8]. The main mechanism, which may explain the great number of
biological effects played by MLT, including anticancer cytotoxic activity,
immunostimulatory action, modulation of blood pressure in a hypotensive way,
and cardio-neuroprotective properties [8] may be simply explained on the basis
of the ability of MLT to modulate DNA expression [8].
A diminished MLT
secretion with a progressive loss of its physiological light/dark rhythm has
been observed in most human systemic diseases, including depression, autism,
schizofrenia [8], autoimmune diseases [17], essential hypertension [18], brain
and cardiac ischemic disorders [19,20], and namely in tumors [8,21], by
representing the main cancer-related endocrine deficiency. Because of its well
documented cytotoxic antiproliferative action [8], and immunostimulatory
activity on the anticancer immunity [21], cancer progression-related MLT
deficiency would not simply represent an epiphenomenon, but it would be
responsible at least in part for cancer growth and diffusion themselves.
The question is to
identify a possible connection between the decreased MLT secretion and enhanced
HCY production, which have been described in the main human systemic
pathologies. Unfortunately, no study has been performed up to now to
concomitantly evaluate MLT and HCY blood concentrations. Then, at present it is
possible only to elaborate some hypotheses on the basis of the biological
properties of MLT and HCY. Some preliminary experimental studies have shown
that MLT may inhibit HCY activity and production (22). Then, because of the
potential inhibitory action of MLT on HCY secretion and toxicity, it is
probable that the systemic disease-associated enhanced production of HCY may
simply depends on the concomitant decline in MLT secretion, also reported in
the literature in the same pathologies [17-21]. Moreover, MLT could reduce HCY
levels, whereas HCY cannot replace MLT deficiency. Then, it is possible to
suggest that MLT deficiency may precede and determine the abnormal production
of HCY.
The most important human
severe systemic diseases, including cancer, brain and cardiac ischemia,
neuropsychiatric pathologies, and essential hypertension, have appeared to be
characterized by two major constant alterations, consisting of enhanced HCY
production and diminished nocturnal secretion of the pineal hormone MLT.
Then,the question is to establish which causative connection may exist between
these two fundamental biological systemic alterations. However, since MLT has
been proven to counteract HCY activity and production [22,23], it is probable
that the primary alteration is consisting of the progressive decline in pineal function
and MLT secretion, as physiologically occurring with the age [8], while the
increase in HCY levels may simply represent the consequence of a diminished
inhibitory effect of the pineal gland on HCY production. Then, MLT therapy
could constitute a new possibile therapy of hyper-homocysteinemia [23].