Publication: On the mechanism of homocysteine pathophysiology and pathogenesis: a unifying hypothesis
Authors
Zhu, B.T.
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Publisher
Murcia : F. Hernández
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DOI
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info:eu-repo/semantics/article
Description
Abstract
Studies have shown that hyperhomocysteinemia
is an important and independent risk factor
for a variety of human cardiovascular diseases. In this
paper, a unifying hypothesis is proposed which suggests
that hyperhomocysteinemia may exert its pathogenic
effects largely through metabolic accumulation of Sadenosyl-
L-homocysteine, a strong noncompetitive
inhibitor of the catechol-O-methyltransferase (COMT)-
mediated methylation metabolism of various catechol
substrates (such as catecholamines and catechol
estrogens). In the case of endogenous catecholamines in
peripheral tissues, inhibition of their methylation by Sadenosyl-
L-homocysteine will result in elevation of
blood or tissue levels of catecholamines, and
consequently, over-stimulation of the cardiovascular
system’s functions. Moreover, because the vasculature is
constantly exposed to high levels of endogenous
catecholamines (due to high levels of circulating
neurohormone epinephrine plus rich innervation with
sympathetic nerve terminals), vascular endothelial cells
would incur chronic cumulative damage caused by the
large amounts of the oxidative products (catechol
quinones/semiquinones and oxyradicals) generated from
endogenous catecholamines. This mechanistic
explanation for the vascular toxicity of
hyperhomocysteinemia is supported by many
experimental findings, and it also fully agrees with the
known protective effects of folate, vitamins B6 and B12
in hyperhomocysteinemic patients. In addition, based on
the predictable effects of hyperhomocysteinemia on the
methylation of catecholamines in the central nervous
system as well as on the methylation of catechol
estrogens in estrogen target organs, it is also suggested that hyperhomocysteinemia is an important risk factor
for the development of neurodegerative disorders
(Parkinson’s and Alzheimer’s diseases) and estrogeninduced
hormonal cancers. More studies are warranted
to test these intriguing ideas.
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