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Betaine:homocysteine
methyltransferase--a new assay for the liver enzyme and its
absence from human skin fibroblasts and peripheral blood
lymphocytes.
Wang JA; Dudman NP; Lynch J; Wilcken DE Department of
Cardiovascular Medicine, Prince Henry Hospital, University of
New South Wales, Sydney, Australia. Clin Chim Acta
(NETHERLANDS) Dec 31 1991, 204 (1-3) p239-49,
Chronic elevation of plasma homocysteine is associated
with increased atherogenesis and thrombosis, and can be
lowered by betaine (N,N,N-trimethylglycine) treatment which
is thought to stimulate activity of the enzyme
betaine:homocysteine methyltransferase. We have developed a
new assay for this enzyme, in which the products of the
enzyme-catalysed reaction between betaine and homocysteine
are oxidised by performic acid before being separated and
quantified by amino acid analysis. This assay confirmed that
human liver contains abundant betaine:homocysteine
methyltransferase (33.4 nmol/h/mg protein at 37 degrees C, pH
7.4). Chicken and lamb livers also contain the enzyme, with
respective activities of 50.4 and 6.2 nmol/h/mg protein.
However, phytohaemagglutinin-stimulated human peripheral
blood lymphocytes and cultured human skin fibroblasts
contained no detectable betaine:homocysteine
methyltransferase (less than 1.4 nmol/h/mg protein), even
after cells were pre-cultured in media designed to stimulate
production of the enzyme. The results emphasize the
importance of the liver in mediating the lowering of elevated
circulating homocysteine by betaine.
Dimethylglycine and chemically
related amines tested for mutagenicity under potential
nitrosation conditions.
Hoorn AJ Hazleton Biotechnologies, Veenendaal, The
Netherlands. Mutat Res (NETHERLANDS) Apr 1989, 222 (4)
p343-50, ISSN 0027-5107
Dimethylglycine (DMG) and the chemically related amino
acids glycine, sarcosine (monomethylglycine) and betaine
(trimethylglycine) were tested in Salmonella typhimurium
strain TA100 after treatment with sodium nitrite under acidic
conditions using a modified Ames Salmonella/microsome assay
as reported by Colman et al. (1980). The increase in the
number of revertants observed both with and without metabolic
activation was also induced in the control mixtures without
adding the amines. From the subsequent testing of the
individual components of the mixtures, we concluded that
non-consumed nitrite was responsible for the mutagenic
responses observed in the different reaction mixtures, and
not the amines themselves. There were no consistent
indications of mutagenic activity of the DMG test mixture as
compared to the control mixture which exhibited both
consistent mutagenic activity and a toxic effect which was
not increased by the addition of DMG. In fact, DMG seemed to
decrease the toxicity of the control reaction solution to the
Salmonella which was clearly observed at the higher doses.
DMG cannot be considered mutagenic under the test conditions
employed. The same can be said of the other amino acids as
well.
[Cholagogic effect of
trimethylglycine in normal animals of different ages and in
experimental atherosclerosis]
Zhelchegonnyi effekt trimetilglitsina u zhivotnykh raznogo
vozrasta v norme i pri eksperimental'nom ateroskleroze.
Zapadniuk VI; Panteleimonova TN Biull Eksp Biol Med (USSR)
Jul 1987, 104 (7) p30-2, ISSN 0365-9615
Trimethylglycine at a dose of 1.5 g/kg was found to
produce marked bile secretory effect in young and old rats.
In rabbits with experimental atherosclerosis,
trimethylglycine increased the content of biliary acids in
the bile and normalized the indexes of lipid metabolism in
the blood serum. Apparently, the effect on cholesterol
transformation into biliary acids and its excretion with the
bile is one of the mechanisms of anti-atherosclerotic action
of trimethylglycine.
[Corrective effect of
trimethylglycine on the nicotinamide coenzyme and adenine
nucleotide content of the tissues in experimental
atherosclerosis]
Korrigiruiushchee vliianie trimetilglitsina na soderzhanie
nikotinamidnykh kofermentov i adeninnukleotidov v tkaniakh
pri eksperimental'nom ateroskleroze. Zapadniuk VI; Chekman
IS; Panteleimonova TN; Tumanov VA Farmakol Toksikol (USSR)
Jul-Aug 1986, 49 (4) p71-3, ISSN 0014-8318
Experiments on adult rabbits with experimental
atherosclerosis induced by cholesterol (0.25 g/kg for 90
days) showed that chronic administration of trimethylglycine
(1.5 g/kg for 30 days) prevented a decrease of the liver and
myocardium content of nicotinamide coenzymes and adenine
nucleotides.
Homocystinuria due to
cystathionine beta-synthase deficiency--the effects of
betaine treatment in pyridoxine-responsive
patients.
Wilcken DE; Dudman NP; Tyrrell PA Metabolism (UNITED
STATES) Dec 1985, 34 (12) p1115-21, ISSN 0026-0495
Homocystinuria due to cystathionine beta-synthase
deficiency may be responsive to pyridoxine, a precursor of
the cofactor pyridoxal phosphate, and the amount of residual
enzyme activity present is the probable determinant of this.
In six treated pyridoxine-responsive patients whose
biochemical control of fasting plasma amino acid levels
appeared optimal, we assessed the effects on plasma amino
acids of standard oral methionine loads (4g/m2 of body area)
before and after adding betaine (trimethylglycine) 6 g/d, to
the treatment regimen of pyridoxine and folic acid. Our aim
was to define the capacity of these patients to metabolize
methionine and to determine whether betaine would effect a
reduction in postload homocysteine levels. During the 24
hours after the methionine challenge all patients had higher
plasma methionine and homocysteine and lower cysteine than
did 17 normal subjects. After betaine these homocysteine
responses were reduced to near normal, and there was a trend
toward increased methionine. There was a direct correlation
between premethionine fasting homocysteine and mean
homocysteine responses during the 24 hours following the
methionine load, both before (r = 0.79) and after betaine (r
= 0.71). Betaine also increased plasma cysteine levels in
patients with the more severe biochemical abnormalities.
After betaine there were modest increases in plasma serine
(mean increase 25%; P less than 0.025). Since the vascular
complications of homocystinuria are related to increased
plasma homocysteine, betaine therapy may reduce this risk in
patients receiving a standard pyridoxine and folic acid
regimen in whom there are abnormal homocysteine responses
after a standard methionine load.
Prevention of strychnine-induced
seizures and death by the N-methylated glycine derivatives
betaine, dimethylglycine and sarcosine.
Freed WJ Pharmacol Biochem Behav (UNITED STATES) Apr 1985,
22 (4) p641-3, ISSN 0091-3057 Journal Code: P3Q
Betaine (N,N,N-trimethylglycine) and N,N-dimethylglycine
have been reported to have anticonvulsant properties in
animals. The purpose of the present study was to determine
whether these compounds can antagonize strychnine-induced
seizures when administered intraperitoneally and to compare
their effects with those of sarcosine (N-methylglycine) and
glycine. Betaine, N,N-dimethylglycine and sarcosine were
equipotent in decreasing the incidence of seizures and death,
causing a 38 to 72 percent decrease in the incidence of
seizures and death at a dosage of 5 mmole/kg. Glycine had no
effect. Thus anticonvulsant activity is conferred to glycine
by a single N-methylation.
[Effect of trimethylglycine on
lipid metabolism in experimental atherosclerosis in
rabbits]
Vliianie trimetilglitsina na lipidnyi obmen pri
eksperimental'nom ateroskleroze u krolikov. Panteleimonova
TN; Zapadniuk VI Farmakol Toksikol (USSR) Jul-Aug 1983, 46
(4) p83-5, ISSN 0014-8318
It has been shown in adult rabbits aged 8 months with
experimental cholesterol atherosclerosis that administration
of trimethylglycinee in a dose of 0.5 g/kg reduces the
elevated content of total and ester-bound cholesterol,
beta-lipoproteins, total lipids in the blood serum and that
of total cholesterol and triglycerides in the liver. Little
toxicity and high efficacy of trimethylglycin in experimental
atherosclerosis make this compound prospective in the light
of its use as an antisclerotic agent.
Amelioration of ethionine toxicity
in the chick.
Lowry KR; Baker DH Department of Animal Sciences,
University of Illinois, Urbana 61801. Poult Sci (UNITED
STATES) Jun 1987, 66 (6) p1028-32, ISSN 0032-5791
Several chick bioassays were conducted to evaluate means
of ameliorating ethionine toxicity. Supplementing a corn-soy
diet marginally deficient in sulfur amino acids (methionine +
cystine) with .075% D,L-ethionine reduced weight gain in
8-day-old chicks by 70% compared to gains of unsupplemented
controls. Dietary addition of .50% DL-methionine prevented
reduction in weight gain and feed intake resulting from
ethionine supplementation whereas feeding supplemental
L-cystine was without effect. Supplementation of the
ethionine-containing diet with either choline or betaine
ameliorated the growth depression, although neither compound
was able to completely overcome the toxic effects of
ethionine. Dietary ethionine did not affect plasma levels of
free methionine or cystine but did increase plasma free
glycine 6-fold. Dietary addition of .50% DL-methionine caused
normalization of plasma glycine levels whereas it elevated
plasma methionine concentration. Although results suggested
the possibility of ethionine-induced serine or threonine
deficiency, dietary additions of .75% L-serine or .75%
L-threonine failed to improve chick weight gain. These
studies suggest that ethionine, in addition to affecting
transsulfuration and transmethylation activity may exert
specific effects on certain amino acids in tissue
pools.
Effects of betaine on seizures in
the rat.
Ghoz EH; Freed WJ Pharmacol Biochem Behav (UNITED STATES)
Apr 1985, 22 (4) p635-40, ISSN 0091-3057 Journal Code:
P3Q
The ability of betaine to block homocysteine,
pentylenetetrazol, and electroshock induced seizures in mice
has previously been observed. In this study, betaine
administered IP and intraventricularly to rats blocked
pentylenetetrazol-induced seizures, but IP betaine did not
block audiogenic seizures. Intraventricular betaine was about
1000-fold more potent than IP betaine in blocking PTZ-induced
seizures. Glycine, a component of the betaine molecule, was
ineffective. It is concluded that betaine has an appreciable
but selective effect in controlling experimental seizures in
rats. This effect is mediated directly by the brain, and is
not due to metabolism of betaine to glycine.
Serum betaine,
N,N-dimethylglycine and N-methylglycine levels in patients
with cobalamin and folate deficiency and related inborn
errors of metabolism
Allen R.H.; Stabler S.P.; Lindenbaum J. Division of
Hematology, Colorado Univ. Health Sciences Ctr., Campus Box
B170, 4200 E Ninth Ave, Denver, CO 80262 USA METAB. CLIN.
EXP. (USA) , 1993, 42/11 (1448-1460)
Homocysteine and 5-CH3-tetrahydrofolate (5-CH3-THF) are
converted to methionine and THF by the CH3-cobalamin
(CH3-Cbl)-dependent enzyme methionine synthase. Serum
homocysteine levels are elevated in more than 95% of patients
with Cbl or folate deficiency and in patients with inborn
errors involving the synthesis of 5-CH3-THF or CH3-Cbl.
Homocysteine and betaine are converted to methionine and
N,N-dimethylglycine by betaine-homocysteine
methyltransferase. It requires neither Cbl nor folate,
although N,N- dimethylglycine is converted to N-methylglycine
and then to glycine in reactions that both involve the
formation of 5,10-CH2-THF from THF. Large amounts of betaine
are often given orally to patients with inborn errors, even
though little is known about its metabolism in normal
subjects or these patients. Thus we developed new gas
chromatographic-mass spectrometric assays for serum betaine,
N,N-dimethylglycine, and N-methylglycine. In 60 blood donors,
we found ranges for normal serum of 17.6 to 73.3, 1.42 to
5.27, and 0.60 to 2.67 micromol/L for the three metabolites,
respectively, which were normal in the majority of 50
patients with Cbl deficiency, none of whom had increased
levels of N-methylglycine. In 25 patients with folate
deficiency, serum betaine level was normal in most, but 76%
and 60% had elevations of N,N-dimethylglycine and
N-methylglycine levels that ranged as high as 343 and 43.2
micromol/L, respectively. All of seven patients on betaine
therapy for inborn errors had high values for betaine (167 to
3,900 micromol/L), N,N- dimethylglycine (15.1 to 250
micromol/L), and N-methylglycine (2.93 to 49.3 micromol/L).
Serum total homocysteine levels remained very high at 47.2 to
156 micromol/L (normal, 5.4 to 16.2). In patients with cbl C
and cbl D mutations, methionine levels remained low or
low-normal at 8.3 to 15.6 micromol/L (normal, 13.3 to 42.7)
despite betaine treatment. We conclude that (1) betaine
levels are maintained in most patients with Cbl and folate
deficiency; (2) levels of N,N-dimethylglycine and
N-methylglycine are increased in most patients with folate
deficiency; and (3) betaine therapy is relatively ineffective
in patients with defective synthesis of CH3-Cbl.
Characterization of betaine
efflux from rat liver mitochondria
Porter R.K.; Scott J.M.; Brand M.D. Department of
Biochemistry, University of Cambridge, Cambridge CB2 1QW
United Kingdom BIOCHIM. BIOPHYS. ACTA BIOENERG. (Netherlands)
, 1993, 1141/2-3 (269-274)
In order to investigate the control of endogenous betaine
supply to the cytoplasmic enzyme betaine-homocysteine
methyltransferase, it was necessary to understand how betaine
synthesized within the mitochondrial matrix is transported
across the mitochondrial inner membrane. Mitochondria were
loaded with radiolabelled betaine and efflux was measured in
a medium at physiological ionic strength. Efflux of
radiolabelled betaine occurred continuously within time. The
efflux rate was unaffected by the presence or absence of a
source of energy except at high membrane potentials, where
betaine efflux rate increased 2-3 fold. Titration of the
membrane potential demonstrated a non-ohmic relationship
between betaine efflux rate and membrane potential. The rate
of betaine efflux was proportional to the matrix betaine
concentration up to 9 mM. Efflux was unaffected by addition
of analogues of betaine and known mitochondrial transport
inhibitors. N-Ethylmaleimide did inhibit efflux by 50%, but
evidence suggested that the effect was non-specific. The lack
of saturability or other evidence for a transport system
suggests that betaine escapes from mitochondria by simple
diffusion. The relative diffusion rates of glycine,
sarcosine, dimethylglycine and betaine suggest that
increasing the degree of N-methylation lowers diffusion
rate.
Metabolism of
S-adenosylmethionine in rat hepatocytes: Transfer of methyl
group from S-adenosylmethionine by methyltransferase
reactions
Tsukada K.; Abe T.; Kuwahata T.; Mitsui K. Department of
Pathological Biochemistry, Medical Research Institute, Tokyo
Medical and Dental University, Tokyo 101 JAPAN LIFE SCI.
(USA) , 1985, 37/7 (665-672)
Treatment of rats with a methionine diet leads not only to
a marked increase of S-adenosylmethionine synthetase in
liver, but also to the increase of glycine, guanidoacetate
and betaine-homocysteine methyltransferases. The activity of
tRNA methyltransferase decreased with the increased amounts
of methionine in the diets. However, the activities of
phospholipids and S-adenosylmethionine-homocysteine
methyltransferases did not show any significant change. When
hepatocarcinogenesis induced by 2-fluorenylacetamide
progresses, the activities of glycine and guandioacetate
methyltransferases in rat liver decreased, and could not be
detected in tumorous area 8 months after treatment. The
levels of S-adenosylmethionine in the liver also decreased to
levels of one-fifth of control animals at 8 months. The
uptake and metabolism of (methyl-sup 3H)-methionine and
-S-adenosylmethionine have been investigated by in vivo and
isolated hepatocytes. The uptake of methionine and transfer
of methyl group to phospholipid in the cells by methionine
were remarkably higher than those by S-adenosylmethionine.
The results indicate that phospholipids in hepatocytes accept
the methyl group from S-adenosylmethionine immediately, when
it is synthesized from methionine, before mixing its pool in
the cells.
Effect of cobalamin inactivation
on folate-dependent transformylases involved in purine
synthesis in rats
Deacon R.; Perry J.; Lumb M.; Chanarin I. Haematology
Section, M.R.C. Clinical Research Centre, Northwick Park
Hospital, Harrow, Middx. HA1 3UJ UNITED KINGDOM BIOCHEM. J.
(ENGLAND) , 1985, 227/1 (67-71)
Nsub 2O oxidizes and inactivates cob(I)alamin, and animals
exposed in this way serve as models for cobalamin
'deficiency'. Such animals show a fall in activity of
glycinamide ribotide transformylase and a rise in that of
5-amino-4-imidazolecarboxamide ribotide transformylase. The
fall in glycinamide ribotide transformylase activity was
prevented by parenteral 5'-methylthioadenosine derived from
methionine. Methylthioadenosine in turn is converted into
formate. Activity of glycinamide ribotide transformylase
recovers after 7 days despite continued Nsub 2O inhalation,
and this is probably related to restoration of methionine
synthesis by induction of betaine:homocysteine
transmethylase.
Labile methyl group balances in
the human: The role of sarcosine
Mudd S.H.; Ebert M.H.; Scriver C.R. Lab. Gen. Comp.
Biochem., Nat. Inst. Ment. Hlth, Bethesda, Md. 20014 USA
METAB. CLIN. EXP. (USA) , 1980, 29/8 (707-720)
Estimates of the daily rate of methionine utilization by
adult humans, published previously, were underestimated
because available data did not permit quantitative assessment
of the rate at which the methyl moiety of methionine is
oxidized. The present paper reports efforts to measure the
rate of oxidation of methionine methyl by the two pathways
that proceed through the intermediate N-methylglycine
(sarcosine). Two sarcosinemic, sarcosinuric patients, proven
or presumed to have specific genetic defects in the
sarcosine-oxidizing system, were studied while maintained on
constant diets containing differing amounts of methionine,
choline (or choline derivatives), and glycine. The
steady-state excretions of sacrosine, creatinine, creatine,
and a number of other materials were determined. The results
obtained suggest that sacrosine is formed in two ways: (1) In
an amount equivalent to the dietary intake of choline (or
choline derivative)-this pathway would make a net positive
contribution to the methionine-methyl pool due to the
transfer of a methyl group from betaine to homocysteine; and
(2) By processes requiring net consumption of methionine
methyl. For the single patient for whom reasonably complete
data were attained, it appears that 2 such processes may be
occurring. One proceeds at a rate (approximately 2 mmole/24
hr) that changed little as total intake of labile methyl
groups was altered. The second became prominent (and
accounted for the bulk of the incremental intake of labile
methyl groups) when this intake exceeded the combined amounts
required for the synthesis of creatine (10.2 mmole/24 hr),
other transmethylation reactions (1.4 mmole/24 hr), polyamine
synthesis (0.5 mmole/24 hr), and the 'basal' process of
sarcosine formation just mentioned (2 mmole/24 hr). It is
possible that such 'basal' sarcosine formation is due chiefly
to endogenous choline synthesis, balanced by degradation,
whereas the more responsive process of sarcosine formation
may be due chiefly to methylation of glycine. Together with
available data, these new data on methionine consumption due
to sarcosine formation permit calculation of a turnover time
for S-adenosylmethionine in human liver (no more than 3.5-7
min), as well as upward revision of previous minimal
estimates of the rate of methylneogenesis, the number of
times the average homocysteinyl moiety cycles between
methionine and homocysteine during its passage through the
body, and the partitioning of homocysteine between the
remethylation and the transsulfuration pathways.
Changes in plasma glucose and
liver glycogen following the administration of gluconeogenic
precursors to the starving fowl
Davison T.F.; Langslow D.R. Houghton Poultry Res. Stat.,
Houghton, Huntingdon UNITED KINGDOM COMP.BIOCHEM.PHYSIOL.
(ENGLAND) , 1975, 52/4a (645-649)
When 6 week old chickens were starved changes in plasma
metabolites indicated that gluconeogenesis was well
established by 48 hr. The ability to induce hyperglycaemia
followed the series lactate > glycerol > pyruvate. The
gluconeogenic activity of amino acids was alanine >
glycine > aspartate > serine > glutamate >
arginine. Lysine and succinate had no gluconeogenic activity.
Only serine stimulated an increase in liver glycogen
stores.
Effect of exogenous proline,
betaine, and carnitine on growth of Listeria monocytogenes in
a minimal medium
Beumer R.R.; Te Giffel M.C.; Cox L.J.; Rombouts F.M.; Abee
T. Laboratory of Food Microbiology, Agricultural University,
Bomenweg 2, 6703 HD Wageningen Netherlands APPL. ENVIRON.
MICROBIOL. (USA) , 1994, 60/4 (1359-1363)
Three Listeria monocytogenes strains isolated from food or
food- processing environments were used to assess the
response of this species to salinity in a chemically defined
minimal medium. Growth in a minimal medium containing five
essential amino acids and glucose as a carbon and energy
source was comparable to growth in a rich medium (brain heart
infusion broth). In the absence and presence of 3% NaCl the
final cell numbers reached in minimal medium were 109 and 107
CFU/ml, respectively. Growth under the latter conditions
could not be detected by spectrophotometry by measuring A660.
Apparently, this technique was not suitable for these
experiments since the detection level was > 107 CFU/ml.
Exogenously added proline (10 mM), trimethylglycine (betaine)
(1 mM), and beta-hydroxy-gamma-N-trimethyl aminobutyrate
(carnitine) (1 mM) significantly stimulated growth under
osmotic stress conditions in minimal medium at both 37 and
10degreeC. Betaine and carnitine are present in foods derived
from plants and animals, respectively. Therefore, these
compounds can contribute significantly to growth of L.
monocytogenes in various foods at high osmolarities.
Betaine:homocysteine
methyltransferase - A new assay for the liver enzyme and its
absence from human skin fibroblasts and peripheral blood
lymphocytes
Wang J.; Dudman N.P.B.; Lynch J.; Wilcken D.E.L.
Department of Medicine, Prince Henry Hospital, Little Bay,
NSW 2036 Australia CLIN. CHIM. ACTA (Netherlands) , 1991,
204/1-3 (239-250)
Chronic elevation of plasma homocysteine is associated
with increased atherogenesis and thrombosis, and can be
lowered by betaine (N,N,N-trimethylglycine) treatment which
is thought to stimulate activity of the enzyme
betaine:homocysteine methyltransferase. We have developed a
new assay for this enzyme, in which the products of the
enzyme-catalysed reaction between betaine and homocysteine
are oxidised by performic acid before being separated and
quantified by amino acid analysis. This assay confirmed that
human liver contains abundant betaine:homocysteine
methyltransferase (33.4 nmol/h/mg protein at 37degreeC, pH
7.4). Chicken and lamb livers also contain the enzyme, with
respective activities of 50.4 and 6.2 nmol/h/mg protein.
However, phytohaemagglutinin-stimulated human peripheral
blood lymphocytes and cultured human skin fibroblasts
contained no detectable betaine:homocysteine
methyltransferase (< l.4 nmol/h/mg protein), even after
cells were pre-cultured in media designed to stimulate
production of the enzyme. The results emphasize the
importance of the liver in mediating the lowering of elevated
circulating homocysteine by betaine.
Antimicrobial activity of
betaine esters, quaternary ammonium amphiphiles which
spontaneously hydrolyze into nontoxic components
Lindstedt M.; Allenmark S.; Thompson R.A.; Edebo L.
Department of Clinical Bacteriology, University of Goteborg,
Guldhedsgatan 10A, S-413 46 Goteborg Sweden ANTIMICROB.
AGENTS CHEMOTHER. (USA) , 1990, 34/10 (1949-1954)
A series of quaternary ammonium compounds that are esters
of betaine and fatty alcohols with hydrocarbon chain lengths
of 10 to 18 carbon atoms were tested with respect to
antimicrobial activities and rates of hydrolysis. When the
tetradecyl derivatives was tested against some selected
microorganisms, the killing effect was comparable to that of
the stable quaternary ammonium compound
cetyltrimethylammonium bromide. At higher pH values, both the
antimicrobial effect and the rate of hydrolysis of the esters
increased. However, whereas at pH 6 greater than 99.99%
killing of Salmonella typhimurium was achieved with 5
microg/ml in 3 min, the rate of hydrolysis was less than 20%
in 18 h. At pH 7, a similar killing effect was achieved in 2
min and 50% hydrolysis occurred in ca. 5 h. Thus, it is
possible to exploit the rapid microbicidal effect of the
compounds before they hydrolyze. The rate of hydrolysis was
reduced by the presence of salt. The bactericidal effect of
the betaine esters increased with the length of the
hydrocarbon chain of the fatty alcohol moiety up to 18 carbon
atoms. Since the hydrolysis products are normal human
metabolites, the hydrolysis property may extend the use of
these quaternary ammonium compounds as disinfectants and
antiseptics for food and body surfaces.
Cardiovascular risk factors in
the older adult
Kannel W.B. Hospital Practice (USA) , 1996, 31/11
(135-138+143-144+147-148)
The potential benefits of correcting identified
cardiovascular risk factors in the elderly are substantial.
Treatment of hypertension has been shown to reduce morbidity
and mortality, and correction of dyslipidemia prevents
recurrent coronary events. Other measures (e.g., lowering
fibrinogen and homocysteine levels, weight reduction) whose
efficacy in the elderly has not been established are
nevertheless recommended.
S-nitrosation ameliorates
homocysteine-mediated neurotoxicity in primary culture of rat
cortical neurons
Kim W.-K. Division of Neuroscience, Medical Research
Center, Ewha Womans University, Seoul South Korea Korean
Journal of Pharmacology (South Korea) , 1996, 32/2
(169-175)
The reactivity of the sulfhydryl (thiol) group of
homocysteine has been associated with an increased risk of
atherosclerosis, thrombosis and stroke. Thiols also react
with nitric oxide (NO, an endothelium-derived relaxing factor
(EDRF)), forming S-nitrosothiols that have been reported to
have potent vasodilatory and antiplatelet effects and been
expected to decrease adverse vascular effects of
homocysteine. The present study was aimed to investigate
whether the S-nitrosation of homocysteine modulates the
neurotoxic effects of homocysteine. An 18 hour-exposure of
cultured rat cortical neurons to homocysteine (>1 mM)
resulted in a significant neuronal cell death. At comparable
concentrations (<10 mM), however, S-nitrosohomocysteine
did not induce neuronal cell death. Furthermore,
S-nitrosohomocysteine partially blocked NMDA-mediated
neurotoxicity. S-nitrosohomocysteine also decreased
NMDA-mediated increases in intracellular calcium
concentration. The present data indicate that in brain nitric
oxide produced from neuronal and nonneuronal cells can
modulate the potential, adverse properties of
homocysteine.
Hyperhomocystinemia threatens
patients with kidney failure. Are intravenously administered
high dosed vitamins effective?
Schmidt K.A. Weinsbergerstrasse 74, D-50823 Koln Germany
Fortschritte der Medizin (Germany) , 1996, 114/24
(44-45)
Therapy 0160; Mammal 0738; Human 0888; Intravenous drug
administration 0182; Note 0063 DRUG DESCRIPTORS: *vitamin b
group--drug therapy--dt; *vitamin b group--drug
combination--cb; * vitamin b group--drug administration--ad;
*folic acid--drug therapy--dt; *folic acid--drug
combination--cb; *homocysteine--endogenous compound--ec;
*pyridoxine --drug therapy--dt; *pyridoxine--drug
combination--cb; *hydroxocobalamin--drug therapy--dt;
*hydroxocobalamin--drug combination--cb MEDICAL DESCRIPTORS:
*kidney failure--drug therapy--dt; *homocystinuria;
*atherosclerosis drug efficacy; risk factor; human;
intravenous drug administration; note
Homocystinuria: What about mild
hyperhomocysteinaemia?
Van den Berg M.; Boers G.H.J. Institute Cardiovascular
Research, Department of Vascular Surgery, Free University
Hospital, PO Box 7057, 1007 MB Amsterdam Netherlands
Postgraduate Medical Journal (United Kingdom) , 1996, 72/851
(513-518)
Hyperhomocysteinaemia is associated with an increased risk
of atherosclerotic vascular disease and thromboembolism, in
both men and women. A variety of conditions can lead to
elevated homocysteine levels, but the relation between high
levels and vascular disease is present regardless of the
underlying cause. Pooled data from a large number of studies
demonstrate that mild hyperhomocysteinaemia after a standard
methionine load is present in 21% of young patients with
coronary artery disease, in 24% of patients with
cerebrovascular disease, and in 32% of patients with
peripheral vascular disease. From such data an odds ratio of
13.0 (95% confidence interval 5.9 to 28.1), as an estimate of
the relative risk of vascular disease at a young age, can be
calculated in subjects with an abnormal response to
methionine loading. Furthermore, mild hyperhomo-cysteinaemia
can lead to a two- or three-fold increase in the risk of
recurrent venous thrombosis. Elevated homocysteine levels can
be reduced to normal in virtually all cases by simple and
safe treatment with vitamin B6, folic acid, and betaine, each
of which is involved in methionine metabolism. A clinically
beneficial effect of such an intervention, currently under
investigation, would make large-scale screening for this risk
factor mandatory.
Plasma homocyst(e)ine levels and
graded risk for myocardial infarction: Findings in two
populations at contrasting risk for coronary heart
disease
Malinow M.R.; Ducimetiere P.; Luc G.; Evans A.E.; Arveiler
D.; Cambien F.; Upson B.M. Oregon Regional Primate Research
Cen, 505 NW 185th Avenue, Beaverton, OR 97006 USA
Atherosclerosis (Ireland) , 1996, 126/1 (27-34)
Standardized mortality rates for coronary heart disease
(CHD) in men are about 3-fold higher in Northern Ireland than
in France. The differences could not be explained by the
presence of conventional risk factors for atherosclerosis. We
studied in subjects from these two countries, an additional
risk factor, namely, concentration of plasma homocyst(e)ine
which is frequently elevated in patients with CHD. We
measured the plasma concentration of homocyst(e)ine in
survivors of myocardial infarction (MI) and in control
subjects from the Belfast, Strasbourg and Lille regions.
Plasma homocyst(e)ine levels were higher in the Irish than in
the French controls; subjects with MI had higher levels than
controls. Results were compatible with global excess of risk
for MI being graded across the distribution of plasma
homocyst(e)ine concentrations, although the trends lost
significance in Belfast after adjustment for other risk
factors. The higher plasma homocyst(e)ine concentrations we
observed in the Irish population could be the reason for the
different CHD mortality rates. This epidemiological
observation could prompt dietary and vitamin supplementation
studies aimed at decreasing homocyst(e)ine levels as well as
the incidence of arterial occlusive disease, under controlled
conditions in high risk populations.
Effect of homocysteine on copper
ion-catalyzed, azo compound-initiated, and mononuclear
cell-mediated oxidative modification of low density
lipoprotein
Halvorsen B.; Brude I.; Drevon C.A.; Nysom J.; Ose L.;
Christiansen E.N.; Nenseter M.S. Institute for Nutrition
Research, University of Oslo, P.O. Box 1046, Blindern, 0316
Oslo Norway Journal of Lipid Research (USA) , 1996, 37/7
(1591-1600)
Homocysteine is an independent risk factor for
cardiovascular diseases. The mechanisms by which elevated
plasma concentrations of homocysteine are related to the
pathogenesis of atherosclerosis are not fully understood. To
examine whether homocysteine is implicated in atherogenesis
through the modification of low density lipoprotein (LDL),
the effect of homocysteine on the oxidation of LDL was
studied by three different oxidation systems. Thus, LDL was
subjected to Cu2+-catalyzed, azo compound-initiated, and
peripheral blood mononuclear cell-mediated oxidative
modification. The extent of modification was assessed by
measuring the formation of conjugated dienes, lipid
peroxides, thiobarbituric acid-reactive substances, and the
relative electrophoretic mobility. Homocysteine at a normal
plasma concentration (6 *p) showed no effect, whereas a
concentration corresponding to moderate hyperhomocysteinemia
(25 microM) or to concentrations seen in homocystinuria
patients (100, 250, and 500 microM) protected LDL from
modification of the lipid as well as of the protein moiety.
One exception was observed: when the oxidation was initiated
by copper ions, homocysteine at concentrations 6 and 25
microM stimulated the lipid peroxidation of LDL to a small,
but statistically significant extent. High concentrations of
homocysteine showed antioxidative properties as long as the
thiol groups were intact, thereby delaying the onset of the
oxidation. The 1,1-diphenyl-2-picrylhydracyl radical test
demonstrated that homocysteine at concentrations less than or
equal to50 microM possessed marked free radical scavenging
capacity. Finally, LDL isolated from two patients with
homozygous homocystinuria showed similar extent of
Cu2+-catalyzed oxidation as LDL from a group of healthy
control subjects. Taken together, our data suggest that low
concentrations of homocysteine in the presence of copper ions
may enhance the lipid peroxidation of LDL, whereas high
concentrations of homocysteine may protect LDL against
oxidative modification in the lipid as well as in the protein
moiety. Thus, homocysteine-induced atherosclerosis may be
explained by mechanisms other than oxidative modification of
low density lipoprotein.
Hyperhomocysteinemia,
hyperfibrinogenemia, and lipoprotein (a) excess in
maintenance dialysis patients: A matched case-control
study
Bostom A.G.; Shemin D.; Lapane K.L.; Sutherland P.; Nadeau
M.R.; Wilson P.W.F.; Yoburn D.; Bausserman L.; Tofler G.;
Jacques P.F.; Selhub J.; Rosenberg I.H. Jean Mayer USDA,
Human Nutrition Res. Center on Aging, Tufts New England
Medical Center, 711 Washington Street, Boston, MA 02111 USA
Atherosclerosis (Ireland) , 1996, 125/1 (91-101)
Maintenance dialysis patients experience an exceedingly
high incidence of arteriosclerotic cardiovascular disease
(CVD) events that are poorly predicted by traditional CVD
risk factor indices. We evaluated the prevalence of three
non-traditional CVD risk factors i.e. hyperhomocysteinemia,
hyperfibrinogenemia, and lipoprotein(a) (Lp(a)) excess, and
combined hyperhomocysteinemia, hyperfibrinogenemia, and Lp(a)
excess, in maintenance dialysis patients. Fasting total
plasma homocysteine (Hcy), fibrinogen, Lp(a), glucose, and
total and HDL cholesterol levels, and traditional CVD risk
factor (i.e. glucose tolerance, smoking, hypertension,
dyslipidemia) prevalences were assessed in 71 dialysis
patients and 71 age, sex, and race matched Framingham Study
controls free of clinical renal disease, with normal serum
creatinine (less than or equal to 1.5 mg/dl). Mean plasma Hcy
(23.7 vs. 9.9 microM, P = 0.0001), fibrinogen (457 vs. 309
mg/dl, P = 0.0001), and Lp(a) (30 vs. 17 mg/dl, P = 0.0070)
levels were substantially increased in the dialysis patients.
Matched odds ratios (with 95% confidence intervals), dialysis
patients/controls, for hyperhomocysteinemia,
hyperfibrinogenemia, and Lp(a) excess, alone or combined,
were markedly greater in the dialysis patients, with no
evidence of confounding by the traditional CVD risk factors;
hyperhomocysteinemia, 105.0 (29.9 368.9);
hyperfibrinogenemia, 16.6 (6.6 42.0) Lp(a) excess, 3.5
(1.5-8.4); all three combined 35.0 (5.7 199.8). Given in
vitro evidence that Hcy, Lp(a), and fibrinogen interact to
promote atherothrombosis, combined hyperhomocysteinemia,
hyperfibrinogenemia, and Lp(a) excess may contribute to the
high incidence of vascular disease sequelae experienced by
dialysis patients, which is inadequately explained by
traditional CVD risk factors. Controlled, prospective studies
of well- characterized maintenance dialysis cohorts are
urgently required to substantiate this hypothesis.
Prevalence of familial mild
hyperhomocysteinemia
Franken D.G.; Boers G.H.J.; Blom H.J.; Cruysberg J.R.M.;
Trijbels F.J.M.; Hamel B.C.J. Department of Radiology,
University Hospital Nijmegen, Post Box 9101, 6500 HB Nijmegen
Netherlands Atherosclerosis (Ireland) , 1996, 125/1
(71-80)
Previous studies have shown that elevated basal
homocysteine levels are correlated among family members of
patients with coronary vascular disease and juvenile venous
thrombosis. This suggests the possibility of the presence of
inherited basal mild hyperhomocysteinemia (mHH). We studied
homocysteine levels, fasting as well as after methionine
load, among 96 family members of 21 post-load
hyperhomocysteinemic vascular index patients, i.e. 6 parents,
27 offspring, 38 siblings, 19 uncles and aunts and 6 cousins.
In 15 out of 21 screened families post-load mHH was
established in at least one family member. Fasting and
post-load mHH was observed in 19 out of 89 (21%) screened
family members (fasting homocysteine levels not measured in
seven family members), and 31 out of 96 screened family
members (32%), respectively. In 40% of all family members,
post-load mHH was not accompanied by fasting mHH. We conclude
that both fasting and post-load mHH seems to be inherited in
the majority of hyperhomocysteinemic vascular patients.
Thrombosis and systemic lupus
erythematosus: The hopkins lupus cohort
perspective
Petri M. Division of Rheumatology, John Hopkins
University, School of Medicine, 1830 E. Monument Street,
Baltimore, MD 21205 USA Scandinavian Journal of Rheumatology
(Norway) , 1996, 25/4 (191-193)
Vascular damage in systemic lupus erythematosus (SLE)
occurs through vasculitis, premature atherosclerosis, and
hypercoagulability (predominantly due to the antiphospholipid
antibody syndrome). In the Hopkins Lupus Cohort, a
prospective cohort study, the incidence of thrombosis is 2
per 100 person-years of follow-up. Markers of immune-complex
mediated injury (high anti-dsDNA and low C3), atherosclerosis
(hypertension, hyperlipidemia, homocysteine) and
antiphospholipid antibodies (lupus anticoagulant or
anticardiolipin) are independent predictors of thrombosis.
Hydroxychloroquine use is protective against future
thrombosis.
Risk factors related to carotid
intima-media thickness and plaque in children with familial
hypercholesterolemia and control subjects
Tonstad S.; Joakimsen O.; Stensland-Bugge E.; Leren T.P.;
Ose L.; Russell D.; Bonaa K.H. Lipid Clinic, Rikshospitalet,
N-0027 Oslo Norway Arteriosclerosis, Thrombosis, and Vascular
Biology (USA) , 1996, 16/8 (984-991)
To assess the relationship between risk factors for
cardiovascular disease and early atherosclerotic changes in
the carotid artery, we measured carotid intima-media
thickness by B-mode ultrasonography in 61 boys and 29 girls
10 to 19 years old with familial hypercholesterolemia (FH)
and 30 control subjects matched for age and sex. All were
nonsmokers, and all the FH adolescents had a known mutation
in the LDL receptor gene. Mean intima- media thickness in the
far wall of the carotid bulb was greater (P=.03) in the FH
group than in the control subjects: 0.54 mm (95% confidence
interval (CI), 0.52 to 0.56) versus 0.50 mm (95% CI, 0.47 to
0.52). In the entire group, mean and maximum intima-media
thicknesses in the carotid bulb were positively associated
with levels of apolipoprotein B and fibrinogen after control
for pubertal stage (r=.19 to .24; P<.05), as was male
sex. Plasma total homocysteine was similar in the FH and
control groups and was associated with mean and maximum
intima-media thicknesses in the far wall of the common
carotid artery and carotid bulb after control for pubertal
stage (r=.22 to .28; P<.05). With the exception of the
relation between plasma fibrinogen level and mean carotid
bulb intima-media thickness, these associations were
essentially unchanged in stepwise multiple linear regression
analyses, allowing for the entry of BMI and level of HDL
cholesterol into the analysis. Carotid artery plaque was
present in 10% of the children with FH versus none of the
control subjects. Children with plaque had a higher mean
cholesterol-years score than children without plaque. These
findings suggest that the classic lipid and hemostatic risk
factors as well as plasma total homocysteine are associated
with markers of early carotid atherosclerosis from the second
decade of life. B-mode ultrasonography may prove to be a
useful tool in risk stratification of children with FH.
Vascular dysfunction in monkeys
with diet-induced hyperhomocyst(e)inemia
Lentz S.R.; Sobey C.G.; Piegors D.J.; Bhopatkar M.Y.;
Faraci F.M.; Malinow M.R.; Heistad D.D. Department of
Internal Medicine, University of Iowa, Iowa City, IA 52242
USA Journal of Clinical Investigation (USA) , 1996, 98/1
(24-29)
Elevated plasma homocyst(e)ine may predispose to
complications of vascular disease. Homocysteine alters
vasomotor regulatory and anticoagulant properties of cultured
vascular endothelial cells, but little is known about effects
of hyperhomocyst(e)inemia on vascular function in vivo. We
tested the hypothesis that diet-induced moderate
hyperhomocyst(e)inemia is associated with vascular
dysfunction in cynomolgus monkeys. Plasma homocyst(e)ine
increased from 4.0plus or minus0.2 microM when monkeys were
fed normal diet to 10.6plus or minus2.6 microM when they were
fed modified diet (meanplus or minusSE; P = 0.02). Vasomotor
responses were assessed in vivo by quantitative angiography
and Doppler measurement of blood flow velocity. In response
to activation of platelets by intraarterial infusion of
collagen, blood flow to the leg decreased by 42plus or
minus9% in monkeys fed modified diet, compared with 14plus or
minus11% in monkeys fed normal diet (P = 0.008). Responses of
resistance vessels to the endothelium-dependent vasodilators
acetylcholine and ADP were markedly impaired in
hyperhomocyst(e)inemic monkeys, which suggests that increased
vasoconstriction in response to collagen may be caused by
decreased vasodilator responsiveness to platelet-generated
ADP. Relaxation to acetylcholine and, to a lesser extent,
nitroprusside, was impaired ex vivo in carotid arteries from
monkeys fed modified diet. Thrombomodulin anticoagulant
activity in aorta decreased by 34plus or minus15% in
hyperhomocyst(e)inemic monkeys (P = 0.03). We conclude that
diet-induced moderate hyperhomocyst(e)inemia is associated
with altered vascular function.
Hyperhomocysteinemia induced by
folic acid deficiency and methionine load - Applications of a
modified HPLC method
Durand P.; Fortin L.J.; Lussier-Cacan S.; Davignon J.;
Blache D. INSERM CJF 93-10, Lab. de Biochimie des
Lipoproteines, Universite de Bourgogne, 7 bd Jeanne d'Arc,
21033 Dijon Cedex France Clinica Chimica Acta (Netherlands) ,
1996, 252/1 (83-93)
The increasing possibility that homocysteine might be
involved in atherosclerosis in non-homocysteinuric subjects
has required the measurement of low concentrations of this
aminothiol in biological samples. The procedure described
here represents an improvement of different HPLC methods. We
utilized an isocratic HPLC system with fluorescence detection
of plasma total homocysteine derivatized after reaction with
ammonium 7-fluoro-benzo-2-oxa-1,3- diazole-4-sulphonate. With
the help of the rapidly eluting internal standard
N-acetyl-cysteine, the method ensures very good recovery
(similar100%), reproducibility and precision (within-assay:
2.31%; day-to-day: 2.8%) in the physiological concentration
range. This procedure allowed us to validate various animal
models of hyperhomocysteinemia such as dietary folic acid
deficiency in rat and acute methionine loads in rat and
hamster. Using this method, we also confirmed that men have
higher plasma total homocysteine levels than women. Due to
its simplicity and reliability, our procedure is suitable for
routine analysis of total homocysteine and other aminothiols
(cysteine, cysteinyl-glycine and glutathione) in biological
samples, as required in clinical and research
laboratories.
Dietary methionine imbalance,
endothelial cell dysfunction and atherosclerosis
Toborek M.; Hennig B. Dept. of Nutrition and Food Science,
University of Kentucky, Lexington, KY 40506-0054 USA
Nutrition Research (USA) , 1996, 16/7 (1251-1266)
Dietary factors can play a crucial role in the development
of atherosclerosis. High fat, high calorie diets are well
known risk factors for this disease. In addition, there is
strong evidence that dietary animal proteins also can
contribute to the development of atherosclerosis. Atherogenic
effects of animal proteins are related, at least in part, to
high levels of methionine in these proteins. An excess of
dietary methionine may induce atherosclerosis by increasing
plasma lipid levels and/or by contributing to endothelial
cell injury or dysfunction. In addition, methionine imbalance
elevates plasma/tissue homocysteine which may induce
oxidative stress and injury to endothelial cells. Methionine
and homocysteine metabolism is regulated by the cellular
content of vitamins B6, B12, riboflavin and folic acid.
Therefore, deficiencies of these vitamins may significantly
influence methionine and homocysteine levels and their
effects on the development of atherosclerosis.
Homocysteine induced
arteriosclerosis-like alterations of the aorta in
normotensive and hypertensive rats following application of
high doses of methionine
Matthias D.; Becker C.-H.; Riezler R.; Kindling P.H. AG
Zytopathologie, Haus 55, B.-Buch, Robert-Rossle-Str. 10,
D-13125 Berlin Germany Atherosclerosis (Ireland) , 1996,
122/2 (201-216)
Following oral administration of methionine in high doses
to normotensive (NR) and spontaneously hypertensive (SHR)
rats, its degradation product, homocysteine (HC), which is
markedly elevated in serum, exerts an angiotoxic action
directed to the aorta. This is accompanied by considerable
loss of endothelium and degeneration, partly with dissolution
of the media cells with formation of characteristic processes
of the degenerating mitochondria, and by elevated HC and
cystathion (CT) values in the aortic wall. At the arterial
vessels of other organs similar alterations did not occur.
There are quantitative differences between NR and SHR. In
SHR, serum shows higher HC and CT concentrations than in NR,
and the methionine-related aortic alterations are
considerably more pronounced and develop earlier, with the
additional formation of connective tissue. Here, a certain
dependence on the methionine dose is noted, in contrast to
NR, for which the magnitude of the reaction appears to be
more related to the length of time of methionine application.
Additional administration of atherogenic substances
(cholestane-3beta,5alpha,6beta-triol, cholesterol,
angiotensin II, cholic acid with methylthiouracil) in SHR
causes an exacerbation of the methionine-related aortic
alterations. Only cholestane-triol has the same effect on the
aortic wall in NR and SHR, with more accentuation in SHR.
Cholestane-triol has, in NR as well as in SHR, a high
coincidence with methionine-induced morphological reactions
including the formation of mitochondrial processes.
Simultaneous application of these two substances did not
cause a potentiation of the effect. High doses of cholesterol
bring about aortic alterations in SHR but not in NR. Thus, in
addition to the disorder of fat and carbohydrate metabolism,
disturbed protein metabolism is of decisive importance as a
risk factor for coronary and other vascular diseases.
Increased serum level of total
homocysteine in CAPD patients: Despite fish oil
therapy
Holdt B.; Korten G.; Knippel M.; Lehmann J.K.; Claus R.;
Holtz M.; Hausmann S. Universitat Rostock, Klinik fur Innere
Medizin, 18059 Rostock Germany Peritoneal Dialysis
International (Canada) , 1996, 16/SUPPL. 1 (S246-S249)
It has been shown that serum total homocysteine (HC) is a
risk factor for vascular disease which characterizes
endothelial damage. The incidence of vascular disease is
increased in continuous ambulatory peritoneal dialysis (CAPD)
patients. Our aim was to investigate: (1) whether
concentration of HC correlates with atherosclerotic and
inflammatory events, and (2) if fish oil therapy can retard
the disturbance In lipid metabolism which promotes
atherosclerosis. Fourteen patients with various degrees of
impaired peritoneal clearance and lipid metabolism were
observed. In all patients the serum HC was elevated. Seven
patients were treated with fish oil for three months. The
results indicate an average increase of HC (+18%), total
cholesterol (+6.6%), aggregation of erythrocytes (+9%), and
an average decrease of dialysate-to-plasma creatinine (D/P)
ratio (-7%), deformability of erythrocytes (-8%), and
normalization of elevated soluble interleukin-2 receptor
(sIL-2R) values. Regression analysis of all data demonstrated
a significant correlation between HC and parameters of lipid
metabolism and hemorheology. There were no significant
correlations between HC and peritoneal function and serum
cytokine levels. We conclude that the treatment in CAPD
patients with fish oil did not improve the lipid metabolism
disturbances in atherosclerosis and peritoneal function.
Elevated HC confirms the progression of the disease.
Hamocysteine antagonism of
nitric oxide-related cytostasis in Salmonella
typhimurium
De Groote M.A.; Testerman T.; Xu Y.; Stauffer G.; Fang
F.C. Department of Medicine, Univ. Colorado Health Sciences
Ctr., Denver, CO 80262 USA Science (USA) , 1996, 272/5260
(414-417)
Nitric oxide (NO) is associated with broad-spectrum
antimicrobial activity of particular importance in infections
caused by intracellular pathogens. An insertion mutation in
the metL gene of Salmonella typhimurium conferred specific
hypersusceptibility to S-nitrosothiol NO-doner compounds and
attenuated virulence of the organism in mice. The metL gene
product catalyzes two proximal metabolic steps required for
homocysteine biosynthesis. S-Nitrosothiol resistance was
restored by exogenous homocysteine or introduction of the
metL gene on a plasmid. Measurement of expression of the
homocysteine-sensitive metH gene indicated that
S-nitrosothiols may directly deplete intracellular
homocysteine. Homocysteine may act as an endogenous NO
antagonist in diverse processes including infection,
atherosclerosis, and neurologic disease.
Homocysteine, folate, and
vascular disease
Kannel W.B.; Wilson P.W.F. Framingham Heart Study, Boston
University School of Medicine, Boston, MA USA Journal of
Myocardial Ischemia (USA) , 1996, 8/2 (60-63)
Current evidence indicates that the genesis of
atherosclerotic disease is multifactorial. One of the newly
recognized factors that contributes to this process is raised
homocysteine blood levels. A variety of atherosclerotic
processes may be facilitated by elevated homocysteine levels,
including stimulation of smooth muscle cell growth,
impairment of endothelial regeneration, oxidation of LDL
particles, and thrombogenesis. A generic defect may account
for some instances of hyperhomocysteinemia, but the majority
of persons with high levels do not have known genetic defects
to account for their elevations. Low levels of folic acid,
vitamin B12, and pyridoxine appear to underlie most cases of
elevated homocysteine levels. Adding folic acid to the diet
may reduce homocysteine levels, but a link between increasing
folic acid and lower risk of atherosclerotic disease has yet
to be demonstrated in clinical trials. However, increasing
daily folic acid intake is not unjustified in some patients.
Since this may mask B12 deficiency, a supplement of
cobalamin, 1 mg/d, has been proposed. In the final analysis,
a clinical trial is needed to determine the true significance
of hyperhomocysteinemia. Meanwhile, physicians and patients
can consider increasing the daily folate intake by eating
more oranges, leafy vegetables, wheat products, and
cereals.
Ischemic heart
disease
Williams J.P. Department of Anesthesiology, UCLA School of
Medicine, 10833 Le Conte Avenue, Los Angeles, CA 90095 USA
Current Opinion in Anaesthesiology (United Kingdom) , 1996,
9/1 (21-26)
Much has changed in the field of myocardial ischemia over
the past 3 years. The central assumption that coronary artery
disease is synonymous in men and women is under revision.
Increasingly, the medical community is recognizing the
importance of an altered presentation of the myocardial
ischemic syndrome in women. Indeed, the very definition of
ischemia itself is under revision. There is mounting evidence
that ischemia requires a two-stage definition: the first for
biochemical evidence and the second for physiological. The
method by which one makes the diagnosis of ischemia is also
constantly being reviewed. The use of Hotter monitoring for
ischemic diagnosis is still a topic for debate. Specifically,
whether to use two or three leads and where those leads
should be placed remains controversial. In fact, there is
some question now as to not only the importance of silent
ischemia but also whether all angina is ischemia. There is
evidence to suggest that some angina is only memory. The
traditional epidemiological view of coronary atherosclerotic
risk factors is also under review and refinement. An
accelerated rate of decline in ventilatory function, lactose
tolerance, and serum levels of homocysteine are some of the
new epidemiological risk factors that are touted as equal or
superior to the traditional ones for predicting long-term
mortality and morbidity. And what of the role of inflammation
in triggering thrombosis and plaque rupture? Is the incidence
of thrombosis the same wherever an atherosclerotic plaque
occurs? Is fibrinogen an important risk factor? This review
will briefly examine the new findings in each of these areas
and discuss the relevant material where appropriate.
Homocysteine and hemostasis:
Pathogenetic mechanisms predisposing to
Thrombosis
Harpel P.C.; Zhang X.; Borth W. Box 1079, 1 Gustave Levy
Place, New York, NY 10029 USA Journal of Nutrition (USA) ,
1996, 126/4 SUPPL. (1285S-1289S)
Growing evidence suggests that moderately elevated levels
of homocyteine are associated not only with arterial
thrombosis and atherosclerosis but also with venous
thrombosis as well. We have reviewed recent studies that
indicate that homocysteine inhibits several different
anticoagulant mechanisms that are mediated by the vascular
endothelium. The protein C enzyme system appears to be one of
the most important anticoagulant pathways in the blood.
Homocysteine inhibits the expression and activity of
endothelial cell surface thrombomodulin, the thrombin
cofactor responsible for protein C activation. Homocysteine
inhibits the antithrombin III binding activity of endothelial
heparan sulfate proteoglycan, thereby suppressing the
anticoagulant effect of antithrombin III. Homocysteine also
inhibits the ecto-ADPase activity of human umbilical vein
endothelial cells (HUVECS). Because ADP is a potent platelet
aggregatory agent, this action of homocysteine is
prothrombotic. Homocysteine also interferes with the
fibrinolytic properties of the endothelial surface because it
inhibits the binding of tissue plasminogen activator.
Homocysteine stimulates HUVEC tissue factor activity. We have
found that lipoprotein(a) (Lp(a)) also stimulates HUVEC
tissue factor activity. The combination of Lp(a) plus
homocysteine induced more tissue factor activity than either
agent alone. These disruptions in several different vessel
wall-related anticoagulant functions provide plausable
mechanisms for the occurrence of thrombosis in
hyperhomocysteinemia.
Homocysteine and coronary
atherosclerosis
Mayer E.L.; Jacobsen D.W.; Robinson K. Department of
Cardiology, Cleveland Clinic Foundation, 9500 Euclid Avenue,
Cleveland, OH 44195 USA Journal of the American College of
Cardiology (USA) , 1996, 27/3 (517-527)
Homocysteine is increasingly recognized as a risk factor
for coronary artery disease. An understanding of its
metabolism and of the importance of vitamins B6 and B12 and
folate as well as enzyme levels in its regulation will aid
the development of therapeutic strategies that, by lowering
circulating concentrations, may also lower risk possible
mechanisms by which elevated homocysteine levels lead to the
development and progression of vascular disease include
effects on platelets, clotting factors and endothelium. This
review presents the clinical and basic scientific evidence
supporting the risk and mechanisms of vascular disease
associated with elevated homocysteine concentrations as well
as the results of preliminary therapeutic trials.
The effect of reduced glomerular
filtration rate on plasma total homocysteine
concentration
Arnadottir M.; Hultberg B.; Nilsson-Ehle P.; Thysell H.
Department of Medicine, National University Hospital, 101
Reykjavik Iceland Scandinavian Journal of Clinical and
Laboratory Investigation (Norway) , 1996 , 56/1 (41-46)
The concentration of homocysteine in plasma has been shown
to be increased in renal failure, possibly contributing to
the accelerated atherosclerosis observed in uraemic patients.
The aim of the present study was to document the relationship
between plasma total homocysteine (tHcy) concentrations and
glomerular filtration rates (GFR) in highly selected
patients, with renal function ranging from normal to dialysis
dependency. GFR was defined as the plasma clearance of
iohexol; a more accurate method than the creatinine-based
estimations applied in previous studies. Plasma tHcy
concentrations were highly correlated to GFR (r=0.70,
p<0.0001) and were significantly increased already in
moderate renal failure. According to a multiple regression
analysis, GFR and red cell folate concentrations
independently predicted plasma tHcy concentrations, whereas
those of serum creatinine, plasma pyridoxal-5-phosphate,
urine albumin and urine alpha-l-microglobulin (a marker of
tubular damage) did not. Thus, GFR seems to be a better
determinant of plasma tHcy concentration than serum
creatinine concentration. Plasma total cysteine and total
cysteinylglycine concentrations followed the same pattern as
those of tHcy.
Lack of effect of oral
N-acetylcysteine on the acute dialysis-related lowering of
total plasma homocysteine in hemodialysis
patients
Bostom A.G.; Shemin D.; Yoburn D.; Fisher D.H.; Madeau
M.R.; Selhub J. Vitamin Bioavailability Laboratory, J.Mayer
USDA Human Nutrit. Res. Ctr., Tufts New England Medical
Center, 711 Washington Street, Boston, MA 02111 USA
Atherosclerosis (Ireland) , 1996, 120/1-2 (241-244)
Hyperhomocysteinemia refractory to standard B-vitamin
supplementation treatment persists in greater than or equal
to 75% of maintenance dialysis patients, potentially
increasing their risk for atherothrombotic sequelae. We
examined whether predialysis administration of oral
N-acetylcysteine (NAC), which acutely increases the
non-protein bound, dialyzable fraction of plasma
homocysteine, might augment the homocysteine-lowering effect
of dialysis therapy. Predialysis and postdialysis total
plasma homocysteine levels were determined on a control day,
and on a day in which oral NAC (1200 mg) was administered
predialysis in n = 11 maintenance hemodialysis patients.
Although NAC treatment had no significant effect on
hemodialysis removal of plasma homocysteine (P = 0.594), we
observed a 16% reduction (P = 0.033) in non-fasting
prehemodialysis total plasma homocysteine on the NAC
treatment vs. non-treatment day. Longer term,
placebo-controlled confirmation of this finding will be
required to evaluate the possible chronic
homocysteine-lowering efficacy of NAC treatment in
hemodialysis patients.
Homocysteine: Relation with
ischemic vascular diseases
Piolot A.; Nadler F.; Parez N.; Jacotot B. Serv. de Med.
Int.-Nutr.-Metab., CHU Henri-Mondor, 94010 Creteil Cedex
France Revue de Medecine Interne (France) , 1996, 17/1
(34-45)
Homocysteine, a sulfur-containing amino acid, is an
intermediate metabolite of methionine. Patients with
homocystinuria and severe hyperhomocysteinemia develop
premature arteriosclerosis and arterial thrombotic events,
and venous thromboembolism. Studies suggest that moderate
hyperhomocysteinemia can be considered as an independent risk
factor in the development of premature cardiovascular
disease. In vitro, homocysteine has toxic effects on
endothelial cells. Homocysteine can promote lipid
peroxidation and damage vascular endothelial cells. Moreover,
homocysteine interferes with the natural anticoagulant system
and the fibrinolytic system. Homocysteinemia should be known
in patients with premature vascular diseases, especially in
subjets with no risk factors. Folic acid, vitamin B6 can
lower homocysteine levels.
Hyperhomocysteinemia:
Background, diagnosis and treatment
Den Heijer M.; Blom H.J. Ziekenhuis Leyenburg, Afdeling
Hematologie, Postbus 40551, 2504 LN Den Haag Netherlands
Nederlands Tijschrift voor de Klinische Chemie (Netherlands)
, 1996, 21/1 (37-40)
Hyperhomocysteinemia is a disorder of the methionine
metabolism, which is accompanied by elevated blood
homocysteine levels. An increasing number of diseases - such
as atherosclerosis, thrombosis and obstetric complications -
is found to be associated with hyperhomocysteinemia. Over the
last years, also the concept of 'hyperhomocysteinemia' itself
has been changed. Hyperhomocysteinemia is nowadays not
synonymous with heterozygous cystathionine synthase
deficiency anymore, but it is a summary term of an elevated
homocysteine level due to any cause. This conceptual change
leads to changes in diagnosis and treatment. Because there
are no data on clinical trials in the field of
hyperhomocysteinemia we recommend to perform a methionine
loading test only in patients with vascular disease or
thrombosis, without other known causes. In the case of
hyperhomocysteinemia one can give the patient the benefit of
the doubt and prescribe a vitamin supplement. First choice
therapy might be folic acid (after exclusion of vitamin B12
deficiency) whether or not in combination with vitamin
B6.
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