1. Neurosci Lett. 2003 Jul 31;346(1-2):97-100.
L-cysteine sulphinate, endogenous sulphur-containing amino acid, inhibits
rat
brain kynurenic acid production via selective interference with kynurenine
aminotransferase II.
Kocki T, Luchowski P, Luchowska E, Wielosz M, Turski WA, Urbanska EM.
Department of Pharmacology and Toxicology, Medical University, Jaczewskiego
8,
20-090 Lublin, Poland.
In the present study the effect of endogenous sulphur-containing amino
acids,
L-cysteine sulphinate, L-cysteate, L-homocysteine sulphinate and L-homocysteate,
on the production of glutamate receptor antagonist, kynurenic acid (KYNA),
was
evaluated. The experiments comprised the measurements of (a). KYNA synthesis
in
rat cortical slices and (b). the activity of KYNA biosynthetic enzymes,
kynurenine aminotransferases (KATs). All studied compounds reduced KYNA
production and inhibited the activity of KAT I and/or KAT II, thus acting
most
probably intracellularly. L-cysteine sulphinate in very low, micromolar
concentrations selectively affected the activity of KAT II, the enzyme
catalyzing approximately 75% of KYNA synthesis in the brain. L-cysteine
sulphinate potency was higher than other studied sulphur-containing amino
acids,
than L-aspartate, L-glutamate, or any other known KAT II inhibitor. Thus,
L-cysteine sulphinate might act as a modulator of KYNA formation in the
brain.
2. Biochem Biophys Res Commun. 2003 May 23;305(1):94-100.
L-cysteine administration prevents liver fibrosis by suppressing hepatic
stellate cell proliferation and activation.
Horie T, Sakaida I, Yokoya F, Nakajo M, Sonaka I, Okita K.
Pharmaceuticals Research Laboratories, Ajinomoto Co, Inc, 1-1, Suzuki-cho,
Kawasaki-ku, Kawasaki 210-8681, Japan.
Recent studies showed that the function of some amino acids is not only
nutritional but also pharmacological. However, the effects of amino acids
on
liver fibrosis and hepatic stellate cell (HSC) remain unclear. In this
research,
as a result of screening of amino acids using liver fibrosis induced by
DMN
administration, L-cysteine was selected as a suppressor of liver fibrosis.
Furthermore, the number of activated HSCs, which increased in the fibrotic
liver
after DMN administration, was decreased in L-cysteine-fed rats. Treatment
of
freshly isolated HSCs with L-cysteine resulted in inhibition of the increase
in
smooth muscle alpha-actin (alphaSMA) expression by HSCs and BrdU incorporation
into the activated HSCs. These findings suggest that L-cysteine is effective
against liver fibrosis. The mechanism of inhibition of fibrosis in the
liver is
surmized to be direct inhibition of activated HSC proliferation and HSC
transformation by L-cysteine.
3. Russ J Immunol. 2002 Apr;7(1):48-56.
Up-regulation of interferon-gamma production by reduced glutathione, anthocyane
and L-cysteine treatment in children with allergic asthma and recurrent
respiratory diseases.
Chernyshov VP, Omelchenko LI, Treusch G, Vodyanik MA, Pochinok TV, Gumenyuk
ME, Zelinsky GM.
Institute of Pediatrics, Obstetrics and Gynecology, Academy of Medical
Sciences,
Kiev, Ukraine. chernyshov@ukr.net
Negative correlation between serum IgE levels and production of IFN-gamma
by
lymphocytes and positive correlation between serum IgE levels and production
of
IL-4 by lymphocytes was detected in 12 children with allergic asthma and
recurrent respiratory diseases. Deficiency of reduced glutathione in whole
blood
and some disorders in phagocytic and oxidative burst activity of monocytes
were
observed in these children. Use of reduced glutathione, L-cysteine and
anthocyane (Recancostat, Clear Vision, Switzerland) resulted in elevation
of
IFN-gamma production, lymphocyte response to mitogens, NK cell activity,
increase in percentage of naive CD4(+) T lymphocytes (refreshment effect)
and
improvement of clinical status. Positive clinical results were lasted
during 6
months.
4. Proc Nutr Soc. 2000 Nov;59(4):595-600.
Glutathione and immune function.
Droge W, Breitkreutz R.
Department of Immunochemistry, Deutsches Krebsforschungszentrum, Im Neuenheimer
Feld 280, D-69120 Heidelberg, Germany. W.Droege@dkfz-heidelberg.de
The immune system works best if the lymphoid cells have a delicately
balanced
intermediate level of glutathione. Even moderate changes in the intracellular
glutathione level have profound effects on lymphocyte functions. Certain
functions, such as the DNA synthetic response, are exquisitely sensitive
to
reactive oxygen intermediates and, therefore, are favoured by high levels
of the
antioxidant glutathione. Certain signal pathways, in contrast, are enhanced
by
oxidative conditions and favoured by low intracellular glutathione levels.
The
available evidence suggests that the lymphocytes from healthy human subjects
have, on average, an optimal glutathione level. There is no indication
that
immunological functions such as resistance to infection or the response
to
vaccination may be enhanced in healthy human subjects by administration
of
glutathione or its precursor amino acid cysteine. However, immunological
functions in diseases that are associated with a cysteine and glutathione
deficiency may be significantly enhanced and potentially restored by cysteine
supplementation. This factor has been studied most extensively in the
case of
human immunodeficiency virus (HIV)-infected patients who were found to
experience, on average, a massive loss of S equivalent to a net loss of
approximately 4 g cysteine/d. Two randomized placebo-controlled trials
have
shown that treatment of HIV-infected patients with N-acetyL-cysteine caused
in
both cases a significant increase in all immunological functions under
test,
including an almost complete restoration of natural killer cell activity.
It
remains to be tested whether cysteine supplementation may be useful also
in
other diseases and conditions that are associated with a low mean plasma
cystine
level and impaired immunological functions.
5. Toxicol Appl Pharmacol. 2000 Oct 1;168(1):72-8.
gamma-Glutamyl transpeptidase and L-cysteine regulate methylmercury uptake
by
HepG2 cells, a human hepatoma cell line.
Wang W, Clarkson TW, Ballatori N.
Department of Environmental Medicine, University of Rochester School of
Medicine, Rochester, New York 14642, USA.
Mechanisms of methylmercury (MeHg) and inorganic mercury (Hg) uptake
were
examined in HepG2 cells, a human hepatoma-derived cell line. MeHg uptake
was
faster when it was present as the L-cysteine complex, as compared to the
glutathione (GSH), CysGly, gamma-GluCys, d-cysteine, N-acetylcysteine,
l-penicillamine, or albumin complexes. Uptake of MeHg-L-cysteine was independent
of Na(+), stereoselective, and was inhibited by the amino acid transport
system
l substrates l-leucine, l-valine, and l-phenylalanine (5 mM). Moreover,
[(3)H]l-leucine uptake was inhibited by MeHg-L-cysteine, suggesting that
MeHg-L-cysteine is transported into HepG2 cells by an l-type amino acid
carrier.
Uptake of MeHg as the GSH complex (MeHg-SG) was dependent on the extracellular
GSH concentration, and was diminished when cellular gamma-glutamyl
transpeptidase activity was inhibited. Inorganic mercury uptake was slower
than
that of MeHg, but was also sensitive to the type of thiol ligand present.
These
findings demonstrate that mercury uptake by HepG2 cells is dependent on
the
chemical structure of the mercury compound, the thiol ligand, and the
activity
of gamma-glutamyl transpeptidase. gamma-Glutamyl transpeptidase appears
to play
a key role in the disposition of MeHg-SG by facilitating the formation
of
MeHg-L-cysteine, which is readily transported into the cells on an amino
acid-type carrier. Copyright 2000 Academic Press.
6. Amino Acids. 2000;18(4):319-27.
Polyamines and thiols in the cytoprotective effect of L-cysteine and
L-methionine on carbon tetrachloride-induced hepatotoxicity.
Chen W, Kennedy DO, Kojima A, Matsui-Yuasa I.
Department of Food and Nutrition, Faculty of Human Life Science, Osaka
City
University, Osaka, Japan.
The relationship between cellular glutathione (GSH), protein-SH levels,
and
lactate dehydrogenase (LDH), with respect to the effect of polyamines
on the
cytoprotective ability of L-cysteine and L-methionine, the most important
components in the sulfur amino acid metabolic pathway, in carbon tetrachloride
(CCl4)-induced toxicity in isolated rat hepatocytes was studied. CCl4
induced a
LDH release and decreased cellular thiols and polyamines levels but treatment
with L-cysteine and L-methionine reversed these decreases. Treating with
methylglyoxal bis-(guanylhydrazone), MGBG, an irreversible inhibitor of
S-adenosylmethionine decarboxylase, which is a key enzyme in spermidine
and
spermine biosynthesis, and therefore used to deplete cellular polyamines,
prevented the protective effect of L-cysteine and L-methionine, but the
addition
of exogenous polyamines inhibited the influence of MGBG. These results
suggest
that the cytoprotective effect of L-cysteine and L-methionine in CCl4-induced
toxicity were via maintenance of cellular polyamines, GSH and protein-SH
concentrations and prevention of LDH leakage.
7. Z Naturforsch [C]. 2000 Mar-Apr;55(3-4):271-7.
Protective effect of L-cysteine and glutathione on rat brain Na+,K+-ATPase
inhibition induced by free radicals.
Tsakiris S, Angelogianni P, Schulpis KH, Behrakis P.
Department of Experimental Physiology, University of Athens, Medical School,
Greece. stsakir@cc.uoa.gr
The aim of this study was to investigate whether the preincubation of
brain
homogenates with L-phenylalanine (Phe), L-cysteine (Cys) or reduced glutathione
(GSH) could reverse the free radical effects on Na+,K+-ATPase activity.
Two well
established systems were used for the production of free radicals: 1)
FeSO4 (84
microM) plus ascorbic acid (400 microM) and 2) FeSO4, ascorbic acid and
H2O2 (1
mM) for 10 min at 37 degrees C in homogenates of adult rat whole brain.
Changes
in brain Na+,K+-ATPase activity and total antioxidant status (TAS) were
studied
in the presence of each system separately, with or without Phe, Cys or
GSH. TAS
value reflects the amount of free radicals and the capacity of the antioxidant
enzymes to limit the free radicals in the homogenate. Na+,K+-ATPase was
inhibited by 35-50% and TAS value was decreased by 50-60% by both systems
of
free radical production. The enzymatic inhibition was completely reversed
and
TAS value increased by 150-180% when brain homogenates were preincubated
with
0.83 mM Cys or GSH. However, this Na+,K+-ATPase inhibition was not affected
by
1.80 mM Phe, which produced a 45-50% increase in TAS value. It is suggested
that
the antioxidant action of Cys and GSH may be due to the binding of free
radicals
to sulfhydryl groups of the molecule, so that free radicals cannot induce
Na+,K+-ATPase inhibition. Moreover, Cys and GSH could regulate towards
normal
values the neural excitability and metabolic energy production, which
may be
disturbed by free radical action on Na+,K+-ATPase.
8. Comp Biochem Physiol B Biochem Mol Biol. 1997 Feb;116(2):223-6.
L-cysteine metabolism in guinea pig and rat tissues.
Wrobel M, Ubuka T, Yao WB, Abe T.
Department of Biochemistry, Okayama University Medical School, Japan.
Rhodanese, gamma-cystathionase and 3-mercaptopyruvate sulfurtransferase
activities were examined in guinea pig and rat liver, kidney and brain.
In the
liver of both species rhodanese showed the same high range of activity
but in
guinea pig kidney and brain a slightly lower level was determined than
that in
corresponding rat tissues. The 3-mercaptopyruvate sulfurtransferase and
gamma-cystathionase activities in all the investigated tissues of guinea
pig
were significantly lower than those in rat. The sulfane sulfur pool, a
source of
sulfur transferred by rhodanese, can be augmented in vitro in guinea pig
liver,
but not in rat liver when 3-mercaptolactate-cysteine disulfide is used
as a
substrate of gamma-cystathionase.
9. Elevated hepatic gamma-glutamylcysteine synthetase activity and abnormal
sulfate levels in liver and muscle tissue may explain abnormal cysteine
and
glutathione levels in SIV-infected rhesus macaques.
Gross A, Hack V, Stahl-Hennig C, Droge W.
AIDS Res Hum Retroviruses. 1996 Nov 20;12(17):1639-41.
To establish whether the low cysteine and glutathione levels in HIV-infected
patients and SIV-infected rhesus macaques may be consequences of an abnormal
cysteine catabolism, we analyzed sulfate and glutathione levels in macaques.
Muscle tissue (m. vastus lateralis and m. gastrocnemius) of SIV- infected
macaques (n = 25) had higher sulfate and lower glutathione and glutamate
levels than that of uninfected controls (n = 9). Hepatic tissue, in contrast,
showed decreased sulfate and glutathione disulfide (GSSG) levels, and
increased gamma-glutamylcysteine synthetase (gamma-GCS) activity. These
findings suggest drainage of the cysteine pool by increased cysteine catabolism
in skeletal muscle tissue, and by increased hepatic glutathione biosynthesis.
Cachectic macaques also showed increased urea levels and decreased glutamine/urea
ratios in the liver, which are obviously related to the abnormal urea
excretion and negative nitrogen balance commonly observed in cachexia.
As urea production and net glutamine synthesis in the liver are strongly
influenced by proton-generating processes, the abnormal hepatic urea production
may be the direct consequence of the cysteine deficiency and the decreased
catabolic conversion of cysteine into sulfate and protons in the liver.
10. Biochem Pharmacol. 1996 May 3;51(9):1111-6.
Maintenance of hepatic glutathione homeostasis and prevention of
acetaminophen-induced cataract in mice by L-cysteine prodrugs.
Rathbun WB, Killen CE, Holleschau AM, Nagasawa HT.
Department of Ophthalmology, University of Minnesota, Minneapolis, USA.
Administration of acetaminophen (ACP, 3.0 mmol/kg, i.p.) to
beta-naphthoflavone-induced C57 BL/6 mice led to the formation of bilateral
cataracts within 8 hr with a 71% incidence. The hepatic glutathione (GSH)
levels
were reduced 99% and lenticular GSH levels reduced 42% in cataractous
mice.
Cataract formation was completely prevented by the co-administration of
the
L-cysteine prodrugs 2(R, S)-methylthiazolidine-4(R)-carboxylic acid (MTCA)
and
2(R, S)-n-propylthiazolidine-4(R)-carboxylic acid (PTCA) in two divided
i.p.
doses totaling 4.5 mmol/kg. 2-Oxo-L-thiazolidine-4-carboxylic acid (OTCA)
was
nearly equipotent, yielding only one cataract in 16 mice, but
D-ribose-L-cysteine (RibCys, 5/16) and N-acetyl-L-cysteine (NAC, 9/14)
were much
less effective. Hepatic and lenticular GSH were maintained at near normal
levels
by MTCA, PTCA and OTCA. These results suggest that maintenance of adequate
cellular GSH levels in the presence of ACP protects against cataract induction.
11. Jpn J Physiol. 1995;45(5):771-83.
The central effect of L-cysteine on cardiovascular system of the conscious
rat.
Takemoto Y.
Department of Physiology, Hiroshima University School of Medicine, Minami-ku,
Japan.
The hemodynamic effects of intracisternal injection of the nonessential
amino
acid L-cysteine were studied in conscious chronically instrumented rats.
Injections of L-cysteine (0.05-0.2 M in artificial cerebrospinal fluid,
10
microliters) into the cisterna magna dose-relatedly elicited an increase
in
arterial pressure but a decrease in superior mesenteric blood flow as
measured
by an electromagnetic flow probe. Injections of the excitatory amino acid
transmitter L-glutamate at comparable doses caused much the same pressor
and
vasoconstrictor effects as did L-cysteine. Prior I.V. injection of vasopressin
V1-receptor antagonist, (d(CH2)5(1), O-Me-Tyr2, Arg8)-vasopressin (10
micrograms/kg), markedly attenuated the effects of L-glutamate but not
of
L-cysteine. Ganglionic blockade with chlorisondamine (5.0 mg/kg) failed
to
attenuate the effects of either amino acid, whereas an additional intravenous
injection of vasopressin antagonist, completely abolished the effects.
These
results indicate that the circulatory effects of L-cysteine are probably
due to
autonomic nervous activation combined with vasopressin release, unlike
those of
L-glutamate which acts mainly through vasopressin release. L-cysteine
may
contribute to central cardiovascular control, since it induces the marked
circulatory effects comparable to or greater than those of L-glutamate.
12. Eur Surg Res. 1995;27(6):363-70.
Effect of the combination of human thioredoxin and L-cysteine on
ischemia-reperfusion injury in isolated rat lungs.
Wada H, Hirata T, Decampos KN, Hitomi S, Slutsky AS.
Department of Thoracic Surgery, Kyoto University, Japan.
We studied the role of human thioredoxin and L-cysteine in ischemia-reperfusion
lung injury. Thirty adult Wistar rats were allocated to five groups, according
to the drug added to the pulmonary artery flush solution before ischemia
(groups
1 and 2: none; group 3: human thioredoxin; group 4: L-cysteine, and group
5:
human thioredoxin and L-cysteine) and according to the ex vivo ischemic
interval
at 37 degrees C (group 1: no ischemia; groups 2-5: 90 min). After ischemia,
the
lungs were reperfused for 60 min with Krebs-Henseleit solution containing
4%
bovine serum albumin. In nonischemic lungs, the pulmonary arterial pressure,
airway pressure, wet to dry lung weight ratio and the albumin concentration
in
bronchoalveolar fluid were within normal ranges. In contrast, all parameters
of
ischemic untreated lungs were generally poor. Compared to the ischemic
untreated
lungs, treatment with the combination of human thioredoxin and L-cysteine
significantly reduced the wet to dry lung weight ratio (group 2: 9.18
+/- 0.25,
group 5: 7.88 +/- 0.27), and the albumin concentration in the bronchoalveolar
lavage fluid (group 2: 78.3 +/- 17.1 micrograms/ml, group 5: 24.0 +/-
3.8
micrograms/ml). No significant improvement was found in pulmonary arterial
pressure and airway pressure. These results suggested that treatment with
human
thioredoxin (adult T cell leukemia-derived factor) and L-cysteine attenuates
ischemia-reperfusion injury in isolated rat lungs.
13. FASEB J. 1994 Nov;8(14):1131-8.
Functions of glutathione and glutathione disulfide in immunology and
immunopathology.
Droge W, Schulze-Osthoff K, Mihm S, Galter D, Schenk H, Eck HP, Roth S,
Gmunder
H.
Department of Immunochemistry, Deutsches Krebsforschungszentrum, Heidelberg,
Germany.
Even a moderate increase in the cellular cysteine supply elevates the
intracellular glutathione (GSH) and glutathione disulfide (GSSG) levels
and
potentiates immunological functions of lymphocytes in vitro. At low GSSG
levels,
T cells cannot optimally activate the immunologically important transcription
factor NF kappa B, whereas high GSSG levels inhibit the DNA binding activity
of
NF kappa B. The effects of GSSG are antagonized by reduced thioredoxin
(TRX). As
the protein tyrosine kinase activities p56lck and p59fyn are activated
in intact
cells by hydrogen peroxide, they are likely targets for GSSG action. These
redox-regulated enzymes trigger signal cascades for NF kappa B activation
and
transduce signals from the T cell antigen receptor, from CD4 and CD8 molecules,
and from the IL-2 receptor beta-chain. The effector phase of cytotoxic
T cell
responses and IL-2-dependent functions are inhibited even by a partial
depletion
of the intracellular GSH pool. As signal transduction is facilitated by
prooxidant conditions, we propose that the well-known immunological consequences
of GSH depletion ultimately may be results of the accompanying GSSG deficiency.
As HIV-infected patients and SIV-infected rhesus macaques have, on the
average,
significantly decreased plasma cyst(e)ine and intracellular GSH levels,
we also
hypothesize that AIDS may be the consequence of a GSSG deficiency as well.
14. Pharmacology. 1993;46(2):61-5.
Cysteine and glutathione deficiency in AIDS patients: a rationale for
the
treatment with N-acetyL-cysteine.
Droge W.
Division of Immunochemistry, Deutsches Krebsforschungszentrum, Heidelberg,
BRD.
A series of clinical studies and laboratory investigations suggests that
the
acquired immunodeficiency syndrome (AIDS) may be the consequence of a
virus-induced cysteine deficiency. HIV-infected persons at all stages
of the
disease were found to have decreased plasma cystine and cysteine concentrations
and decreased intracellular glutathione levels. In rhesus macaques, cysteine
levels decrease already within 1-2 weeks after infection with the closely
related virus SIVmac. HIV-infected persons and SIV-infected rhesus macaques
have
also, on the average, substantially increased plasma glutamate levels.
Increased
glutamate levels aggravate the cysteine deficiency by inhibiting the membrane
transport of cystine. Even moderately elevated extracellular glutamate
levels as
they occur in HIV-infected persons cause a substantial decrease of intracellular
cysteine levels. Clinical studies revealed that individual cystine and
glutamate
levels are correlated with the individual lymphocyte reactivity and T4+
cell
counts but not T8+ cell counts. This phenomenon was demonstrated not only
in
HIV-infected persons but also in healthy human individuals. The cellular
cysteine supply affects amongst others the intracellular glutathione level
and
IL-2-dependent proliferation of T cells and (inversely) also the activation
of
the transcription factor NF-kappa B. The cysteine deficiency of HIV-infected
persons is, therefore, possibly responsible not only for the cellular
dysfunction but also for the overexpression of tumor necrosis factor-alpha
(TNF-alpha), interleukin-2 receptor alpha-chain, and and beta 2-microglobulin.
All the corresponding genes are associated with kappa-like enhancer
sequences.(ABSTRACT TRUNCATED AT 250 WORDS)
15. Cysteine and glutathione deficiency in HIV-infected patients. The
basis for treatment with N-acetyL-cysteine
Droge W.
AIDS-FORSCHUNG (Germany), 1992, 7/4 (197-199)
Clinical studies and complementary laboratory investigations suggest
that the deterioration of the immune system in HIV-infected patients may
be the consequence of a virus-induced cysteine deficiency. HIV-infected
persons at all stages of the disease have, on the average, decreased plasma
cystine and cysteine and decreased intracellular glutathione levels. Cysteine
levels also decrease in rhesus macaques within 1 to 2 weeks after infection
with SIV(mac). HIV-infected persons and SIV-infected macaques also have,
on the average, markedly increased plasma glutamate levels, which aggravate
the cysteine deficiency by inhibiting the membrane transport of cystine.
Even moderately increased extracellular glutamate levels as they are found
in HIV-infected persons cause a profound decrease of intracellular cyst(e)ine
levels. A correlation between individual T4+ cell counts (but not T8+
cell counts) and individual cystine and glutamate levels has been found
not only in HIV-infected persons but also in healthy individuals, indicating
that the linkage between cysteine supply and immune system is demonstrable
even in the absence of the virus. There is suggestive evidence that the
HIV-induced cysteine deficiency is not only responsible for the 'cellular
dysfunction' but also for the abnormal activation which is exemplified
by the lymphadenopathy syndrome and abnormal antibody production. HIV-infected
persons were found to have abnormally high TNFalpha, IL-2 receptor alpha-chain
and beta2-microglobulin levels. All the corresponding genes are associated
with kappaB-like enhancer sequences. And the activation of the transcription
factor NFkappaB is negatively regulated by cysteine or cysteine derivatives.
We have, therefore, suggested that N-acetyL-cysteine (NAC) may be considered
for the replenishment of cysteine and glutathione levels in HIV-infected
persons, since NAC is a well-established and safe drug with well-documented
pharmacokinetics.
16. Biochem Pharmacol. 1992 Jul 7;44(1):129-35.
Acetaminophen-induced depletion of glutathione and cysteine in the aging
mouse
kidney.
Richie JP Jr, Lang CA, Chen TS.
American Health Foundation, Valhalla, NY 10595.
Glutathione (GSH) plays an essential role in the detoxification of acetaminophen
(APAP) and the prevention of APAP-induced toxicity in the kidney. Our
previous results demonstrated that a GSH deficiency is a general property
of aging tissues, including the kidney, suggesting a hypothesis that senescent
organisms are at greater risk to APAP-induced renal damage. To test this,
C57BL/6NIA mice of different ages through the life span were injected
with various doses of APAP, and the extent of GSH and cysteine (Cys) depletion
and recovery were determined. At time intervals up to 24 hr, kidney cortex
samples were obtained, processed and analyzed for glutathione status,
namely GSH, glutathione disulfide (GSSG), Cys and cystine, using an HPLC
method with dual electrochemical detection. In the uninjected controls,
GSH and Cys concentrations decreased about 30% in the aging mouse, but
the GSSG and cystine levels were unchanged during the life span. APAP
administration depleted the kidney GSH and Cys contents in a dose
17. Biochem Pharmacol. 1992 Feb 4;43(3):483-8.
Cysteine isopropylester protects against paracetamol-induced toxicity.
Butterworth M, Upshall DG, Smith LL, Cohen GM.
Toxicology Unit, School of Pharmacy, University of London, U.K.
Cysteine isopropylester (CIPE), a novel ester of cysteine, has been synthesized
in order to evaluate its potential as a chemoprotectant. The increased
lipophilicity of the ester relative to cysteine should facilitate its
entry into cells where, following hydrolysis, it should act as an intracellular
source of cysteine or be utilized for the synthesis of glutathione so
protecting the cell against various types of chemical insult. In this
study, we evaluate the ability of CIPE to protect against paracetamol-induced
hepatotoxicity in mice. When administered to mice, CIPE produced a rapid
but transient elevation of levels of non-protein sulphydryls (NPSH) in
liver, lung, kidney and spleen. The greatest increase in NPSH was seen
in the lung, but after 60 min all NPSH values had returned to control
levels, demonstrating the capacity of the mouse to rapidly metabolize
both CIPE and cysteine. In mice pretreated with benzo(a)pyrene, CIPE protected
against paracetamol-induced toxicity as measured by the prevention of
18. Blood. 1992 Sep 1;80(5):1247-53.
Antithrombotic properties of L-cysteine,
N-(mercaptoacetyl)-D-Tyr-Arg-Gly-Asp-sulfoxide (G4120) in a hamster
platelet-rich femoral vein thrombosis model.
Imura Y, Stassen JM, Bunting S, Stockmans F, Collen D.
Center for Thrombosis and Vascular Research, University of Leuven, Belgium.
Platelet aggregation plays an important role in the pathogenesis in arterial
thrombotic disorders. The binding of fibrinogen via the Arg-Gly-Asp (RGD)
recognition sequence to the platelet glycoprotein IIb/IIIa (GPIIb/IIIa)
receptor
is an essential step of platelet aggregation induced by various physiologic
agonists, and RGD-containing peptides that bind to the GPIIb/IIIa receptor
inhibit thrombus formation in vivo. L-cysteine,
N-(mercaptoacetyl)D-tyrosyl-L-arginylglycyl-L alpha-aspartyl-cyclic
(1----5)-sulfide, 5-oxide (G4120), a cyclic RGD-containing synthetic
pentapeptide, inhibits adenosine diphosphate (ADP)-induced platelet aggregation
with 50% inhibition (IC50) at a concentration of 0.05 microgram/mL in
human
plasma, 0.12 microgram/mL in hamster plasma, and 11 micrograms/mL in rat
plasma.
Corresponding values for the linear tetrapeptide Arg-Gly-Asp-Phe (RGDF)
were 7
and 100 micrograms/mL in human and hamster plasma. The antithrombotic
effects of
G4120 and RGDF were evaluated in a hamster model consisting of a mural
platelet-rich femoral vein thrombus induced by standardized endothelial
cell
damage. Bolus intravenous injection of G4120 was followed by a biphasic
disappearance of G4120 from plasma with t1/2 alpha of 3.7 minutes and
t1/2 beta
of 63 minutes, corresponding to a plasma clearance of 5.2 +/- 0.68 mL/min.
Bolus
intravenous injection of G4120 inhibited ex vivo platelet aggregation
with 0.5
mumol/L ADP and in vivo thrombus formation in a dose-dependent manner,
with ID50
of 11 and 11 micrograms/kg, respectively. Bolus injection of RGDF inhibited
in
vivo thrombus formation; 43% inhibition was obtained at a dose of 30 mg/kg.
Thus, this hamster platelet-rich femoral vein thrombosis model may be
useful for
the investigation of the antithrombotic properties of platelet GPIIb/IIIa
antagonistic peptides. The cyclic synthetic peptide G4120 appears to have
a very
potent antithrombotic activity in vivo.
19. Effects of amino acids on acute alcohol intoxication in mice--concentrations
of ethanol, acetaldehyde, acetate and acetone in blood and tissues.
Tsukamoto S, Kanegae T, Nagoya T, Shimamura M, Mieda Y, Nomura M, Hojo
K,
Okubo H.
Arukoru Kenkyuto Yakubutsu Ison. 1990 Oct;25(5):429-40.
Condensation reactions between some SH-amino acids (L-and D-cysteine
1%) and acetaldehyde (50 microM) were studied in vitro experiment. In
the aqueous solution, free acetaldehyde was reduced to 41.3% by L-cysteine
and to 36.4% by D-cysteine. In the reaction with human blood medium, after
the medium was deproteinized with perchloric acid reagent, acetaldehyde
was reduced to 47.0% by L-cysteine and to 43.8% by D-cysteine. D-Cysteine
appears to have great stability of reacting acetaldehyde. In vitro experiment
reactability for D-cysteine exhibited 3-8% higher than that for L-cysteine.
Next, effects of some amino acids on alcohol metabolism were studied in
male ICR mice. The animals were given ethanol through a gastric catheter
at a dose of 2 g/kg and they were intraperitoneally injected L- cysteine
(300 mg/kg), D-cysteine (300 mg/kg), L-alanine (300 mg/kg) and control
(saline), respectively in the period of one hour before the injection
of ethanol. Blood and tissues samples were analyzed for ethanol, acetaldehyde,
acetate and acetone during alcohol intoxication in mice by head space
gas chromatography. In the groups administered D-cysteine and L- cysteine,
the mice showed a definitely faster oxidation and disappearance of ethanol.
Especially in the D-cysteine group, ethanol levels in blood, liver and
brain remained lower than that in the other groups (p less than 0.01).
Acetaldehyde levels in blood, liver and brain remained low by L- cysteine.
Ethanol metabolites during alcohol oxidation by chemical reactabilities
of L- and D-cysteine showed different distribution in the mice, respectively.
In the mice received L-alanine, acetate and acetone levels in blood, liver
and brain were distinctly reduced (p less than 0.01). L-Alanine is reported
to supply an abundance of pyruvic acid that performs the NAD-generating
system. NAD produced is introduced to alcohol metabolism and the TCA cycle.
It was thus presumed that the L- or/and D- cysteine, and L-alanine was
effective in acute alcohol intoxication by heavy drinking.
20. Jpn J Cancer Res. 1989 Feb;80(2):182-7.
Enhanced antitumor effect of 5'-deoxy-5-fluorouridine by oral administration
with L-cysteine.
Iigo M, Nakajima Y, Araki E, Hoshi A.
Chemotherapy Division, National Cancer Center Research Institute, Tokyo.
When given orally in combination with L-cysteine, 5'-deoxy-5-fluorouridine
(DFUR) brought about a significant reduction in the growth of adenocarcinoma
755
and a significant prolongation of life-span in mice bearing Lewis lung
carcinoma
without increased toxicity to the host as compared with DFUR alone, though
L-cysteine alone did not show an appreciable antitumor activity. Moreover,
the
combination of DFUR and L-cysteine resulted in a marked retardation of
growth of
human colon tumor LS174T transplanted into nude mice. Thus, the potency
of DFUR
was increased by L-cysteine. Pharmacokinetic studies revealed that after
DFUR
administration, plasma DFUR and 5-fluorouracil (5-FU) levels rapidly declined,
but that, in the combination with L-cysteine, the plasma clearances of
DFUR and
5-FU were slowed down considerably. In the tumor, DFUR and 5-FU levels
were
similar to those in the plasma. Such a prolongation of DFUR and 5-FU levels
in
plasma and tumor may produce the enhancement of antitumor effect seen
with the
combination of DFUR and L-cysteine.
21. Am Rev Respir Dis. 1985 Nov;132(5):1049-54.
Investigation of the protective effects of the antioxidants ascorbate,
cysteine,
and dapsone on the phagocyte-mediated oxidative inactivation of human
alpha-1-protease inhibitor in vitro.
Theron A, Anderson R.
Oxidants derived from the atmosphere or from activated pulmonary phagocytes
mediate functional inactivation of alpha-1-protease inhibitor (alpha-1-PI).
Chronic exposure to these oxidants may cause emphysema. In this study
we have investigated the effects of the antioxidants ascorbate, cysteine
(10(-4) M to 10(-1) M), and dapsone (10(-6) M to 10(-3) M) on the oxidative
inactivation of human alpha-1-PI by leukoattractant-activated polymorphonuclear
leukocytes (PMNL) in vitro. During exposure of alpha-1-PI to stimulated
PMNL in the presence of ascorbate and cysteine at concentrations of greater
than 10(-4) M and dapsone at greater than 10(-6) M, the elastase inhibitory
activity of alpha-1-PI was preserved. However, exposure of the alpha-1-PI
to the antioxidants subsequent to PMNL-mediated oxidative inactivation
was not associated with reactivation of elastase inhibitory capacity.
Ascorbate, cysteine, and dapsone at concentrations that caused 50% protection
of alpha-1-PI did not affect degranulation or the binding of radiolabeled
leukoattractant to PMNL. It is suggested that the protective effects of
the antioxidants are related to their ability to scavenge superoxide and
oxidants generated by the PMNL-myeloperoxidase/H2O2/halide system. Because
the effects of ascorbate and especially those of dapsone were observed
at concentrations of these agents that are attainable in vivo, our results
may have clinical significance
22. J Biol Chem. 1984 May 10;259(9):5606-11.
Free radical metabolites of L-cysteine oxidation.
Harman LS, Mottley C, Mason RP.
The oxidation of L-cysteine by horseradish peroxidase in the presence
of oxygen
forms a thiyl free radical as demonstrated with the spin-trapping ESR
technique.
Reactions of this thiyl free radical result in oxygen consumption, which
is
inhibited by the spin trap 5,5'-dimethyl-1-pyrroline-N-oxide. Cysteine
sulfinic
acid, a cysteine metabolite, is a poorer substrate for horseradish peroxidase
than cysteine and is oxidized to form both sulfur-centered and carbon-centered
free radicals.
23. Preventing Hypoglycemia
Anti-Aging News, January 1982 Vo.2, No. 1 pg 6-7
Cysteine is a strong reducing agent (it can prevent oxidation of some
other substances). In fact, it has been found that too much cysteine in
a cell culture medium can inactivate the hormone insulin contained in
the medium. The insulin molecule contains three disulfide bonds, at least
one of which can be reduced by cysteine. When this happens, the insulin
molecule can no longer maintain the proper shape to function normally
in stimulating the metabolism of sugar. In hypoglycemia attacks, there
is too much insulin and too little sugar in the blood stream. Cysteine
can inactivate insulin, thereby allowing the sugar level to begin to rise
again. We and others have used the combination of vitamins B1, C, and
cysteine to successfully abort severe attacks of hypoglycemia. A reasonable
dose for a healthy adult is 5 grams of C, 1 gram of B1, and 1 gram cysteine.
Although cysteine is a nutrient, it s use on a long-term basis should
be considered experimental. Start with a low dose (250 milligrams per
day) and work your way up. Always use at least three times as much vitamin
C as cysteine. Be sure to consult with your physician and have regular
clinical tests of basic body functions, especially liver and kidney. Diabetics
should not use cysteine supplements due to its anti-insulin effects.
24. Hum Genet. 1979;50(1):51-7.
Chromosomal breakage in Crohn's disease: anticlastogenic effect of
D-penicillamine and L-cysteine.
Emerit I, Emerit J, Levy A, Keck M.
The incidence of chromosome breakage was found to be elevated in 42 patients
with Crohn's disease. This phenomenon was much more striking in cultures
set up
with TCM 199 than in cultures set up with RPMI 1629 rich in L-cysteine.
The drug
D-penicillamine, a close analog of L-cysteine, gave an apparent therapeutic
response in several patients and reduced the chromosome breakage frequency
in
the lymphocytes of these patients in vitro and in vivo.
25. Annu Rev Plant Biol. 2002;53:159-82.
Phytochelatins and metallothioneins: roles in heavy metal detoxification
and
homeostasis.
Cobbett C, Goldsbrough P.
Department of Genetics, University of Melbourne, Parkville, Australia
3052.
ccobbett@unimelb.edu.au
Among the heavy metal-binding ligands in plant cells the phytochelatins
(PCs)
and metallothioneins (MTs) are the best characterized. PCs and MTs are
different
classes of cysteine-rich, heavy metal-binding protein molecules. PCs are
enzymatically synthesized peptides, whereas MTs are gene-encoded polypeptides.
Recently, genes encoding the enzyme PC synthase have been identified in
plants
and other species while the completion of the Arabidopsis genome sequence
has
allowed the identification of the entire suite of MT genes in a higher
plant.
Recent advances in understanding the regulation of PC biosynthesis and
MT gene
expression and the possible roles of PCs and MTs in heavy metal detoxification
and homeostasis are reviewed.
26. J Biol Chem. 2001 Jun 15;276(24):20817-20. Epub 2001 Apr 19.
A new pathway for heavy metal detoxification in animals. Phytochelatin
synthase
is required for cadmium tolerance in Caenorhabditis elegans.
Vatamaniuk OK, Bucher EA, Ward JT, Rea PA.
Department of Biology, Plant Science Institute, University of Pennsylvania,
Philadelphia, Pennsylvania 19104-6018, USA.
Increasing emissions of heavy metals such as cadmium, mercury, and arsenic
into
the environment pose an acute problem for all organisms. Considerations
of the
biochemical basis of heavy metal detoxification in animals have focused
exclusively on two classes of peptides, the thiol tripeptide, glutathione
(GSH,
gamma-Glu-Cys-Gly), and a diverse family of cysteine-rich low molecular
weight
proteins, the metallothioneins. Plants and some fungi, however, not only
deploy
GSH and metallothioneins for metal detoxification but also synthesize
another
class of heavy metal binding peptides termed phytochelatins (PCs) from
GSH. Here
we show that PC-mediated heavy metal detoxification is not restricted
to plants
and some fungi but extends to animals by demonstrating that the ce-pcs-1
gene of
the nematode worm Caenorhabditis elegans encodes a functional PC synthase
whose
activity is critical for heavy metal tolerance in the intact organism.
27. Biol Trace Elem Res. 2000 Jul;76(1):19-30.
Study of the effect of the administration of Cd(II), cysteine, methionine,
and
Cd(II) together with cysteine or methionine on the conversion of xanthine
dehydrogenase into xanthine oxidase.
Esteves AC, Felcman J.
Department of Chemistry, Pontificia Universidade Catolica do Rio de Janeiro,
Rio
de Janeiro, Brazil.
Cadmium is known as to be a potent pulmonary carcinogen to human beings
and to
induce prostate tumor. The sequestration of cadmium, an extremely toxic
element
to living cells, which is performed by biological ligands such as amino
acids,
peptides, proteins or enzymes is important to minimize its participation
in such
deleterious processes. The synthesis of metallothionein is induced by
a wide
range of metals, in which cadmium is a particularly potent inducer. This
protein
is usually associated with cadmium exposure in man. Because metallothioneins
may
act as a detoxification agent for cadmium and chelation involves sulfur
donor
atoms, we administered only cadmium, cysteine, or methionine to rats and
also
each of these S-amino acids together with cadmium and measured the production
of
superoxide radicals derived from the conversion of xanthine dehydrogenase
to
xanthine oxidase. It could be seen in this work that the presence of cadmium
enhances this conversion. However, its inoculation with cysteine or methionine
almost completely diminishes this effect and this can be the result of
the fact
that these amino acids complex Cd(II). Thus, these compounds can be a
model of
the action of metallothionein, removing cadmium from circulation and preventing
its deleterious effect.
28. Altern Med Rev. 1998 Aug;3(4):262-70.
Cysteine metabolism and metal toxicity.
Quig D.
Doctor's Data, Inc., West Chicago, IL, USA. dquig@doctorsdata.com
Chronic, low level exposure to toxic metals is an increasing global problem.
The
symptoms associated with the slow accumulation of toxic metals are multiple
and
rather nondescript, and overt expression of toxic effects may not appear
until
later in life. The sulfhydryl-reactive metals (mercury, cadmium, lead,
arsenic)
are particularly insidious and can affect a vast array of biochemical
and
nutritional processes. The primary mechanisms by which the sulfhydryl-reactive
metals elicit their toxic effects are summarized. The pro-oxidative effects
of
the metals are compounded by the fact that the metals also inhibit antioxidative
enzymes and deplete intracellular glutathione. The metals also have the
potential to disrupt the metabolism and biological activities of many
proteins
due to their high affinity for free sulfhydryl groups. Cysteine has a
pivotal
role in inducible, endogenous detoxication mechanisms in the body, and
metal
exposure taxes cysteine status. The protective effects of glutathione
and the
metallothioneins are discussed in detail. Basic research pertaining to
the
transport of toxic metals into the brain is summarized, and a case is
made for
the use of hydrolyzed whey protein to support metal detoxification and
neurological function. Metal exposure also affects essential element status,
which can further decrease antioxidation and detoxification processes.
Early
detection and treatment of metal burden is important for successful
detoxification, and optimization of nutritional status is paramount to
the
prevention and treatment of metal toxicity.
29. J Nutr. 1987 Jun;117(6):1003-10.
Pharmacologic role of cysteine in ameliorating or exacerbating mineral
toxicities.
Baker DH, Czarnecki-Maulden GL.
Cysteine, via chelation reactions, ameliorates biochemical lesions caused
by
excessive ingestion of several trace elements. Because oral cysteine per
se is
considerably more protective than the in vivo metabolic cysteine precursors,
methionine or cystine, chelation of cysteine with trace elements likely
occurs
primarily in the gut, thereby decreasing absorption of both cysteine and
the
trace element in question. Hence, using copper as an example, orally
administered cysteine markedly improves growth and reduces liver copper
deposition in chicks or rats fed a high level of inorganic copper. Likewise,
excessive copper ingestion impairs sulfur amino acid (SAA) utilization
and
increases the dietary requirement for SAA. Cobalt and selenium toxicities
are
also ameliorated by oral cysteine ingestion, with the responses being
even more
striking than those occurring with copper toxicity. While inorganic arsenic
poisonings are generally ameliorated by administering cysteine or a cysteine
derivative (e.g., dimercaptopropanol), organic pentavalent arsenic toxicity
is
exacerbated by cysteine administration. Cysteine in this instance acts
as a
reducing agent, facilitating conversion of organic pentavalent arsenicals
such
as roxarsone and arsanilic acid to the more toxic trivalent state.
30. J Infect Dis. 2000 Sep;182 Suppl 1:S81-4.
Regulation of cysteine-rich intestinal protein, a zinc finger protein,
by
mediators of the immune response.
Cousins RJ, Lanningham-Foster L.
Food Science and Human Nutrition Department, Center for Nutritional Sciences,
University of Florida, Gainesville, FL 32611-0370, USA.
Cysteine-rich intestinal protein (CRIP), a member of the LIM protein
family, has
a unique double zinc finger motif as the defining feature. CRIP is highly
expressed in intestine and immune cells. CRIP transgenic (Tg) mice and
nontransgenic controls were challenged with lipopolysaccharide (LPS).
Serum
concentrations of interferon-gamma and tumor necrosis factor-alpha were
less
while those of interleukin-6 and -10 were greater in the Tg mice following
LPS
administration. CRIP-overexpressing splenocytes produce the same cytokine
profile. These responses are consistent with a regulatory role for this
protein
in cell differentiation, which produces an imbalance in Th1 and Th2 cytokines.
Stimulation of CRIP protein levels by LPS is eliminated in metallothionein
knockout mice, suggesting metallothionein is the source of zinc for this
zinc
finger protein and, further, that this could reflect a relationship to
the zinc
nutritional status and to the aberrant Th1/Th2 cytokine balance observed
in zinc
deficiency.
31. Am J Med. 1991 Sep 30;91(3C):140S-144S.
Modulation of lymphocyte functions and immune responses by cysteine and
cysteine
derivatives.
Droge W, Eck HP, Gmunder H, Mihm S.
Division of Immunochemistry, Deutsches Krebsforschungszentrum, Heidelberg,
F.R.G.
Mitogenically stimulated human peripheral blood lymphocytes and T cell
clones
were found to have weak membrane transport activity for the disulfide
cystine
but strong membrane transport activity for the thiol amino acid cysteine.
Cysteine, however, is represented at the lowest concentration among all
protein-forming amino acids in the blood plasma. Complementary laboratory
experiments have shown that the cysteine supply is indeed limiting for
important
lymphocyte functions. Proliferative responses of mitogenically stimulated
lymphocytes and T-cell clones and the activation of cytotoxic T cells
in
allogeneic mixed lymphocyte cultures are strongly influenced by small
variations
in the extracellular cysteine concentration even in the presence of relatively
high and approximately physiologic concentrations of cystine. Cysteine
can be
substituted by N-acetylcysteine but not by cystine. The more detailed
analysis
revealed that the extracellular supply of cysteine influences strongly
the
intracellular level of glutathione (GSH) and also the activity of the
transcription factor NF kappa B that regulates the expression of several
immunologically relevant genes. In vitro experiments including double-chamber
experiments with macrophages and lymphocytes revealed, moreover, that
cysteine
plays an important role as a regulatory mediator between these cell types.
The
cysteine supply is impaired directly or indirectly in several pathologic
conditions that are associated with immunodeficiencies, including the
acquired
immune deficiency syndrome (AIDS). Cysteine or cysteine derivatives may
therefore be considered for the treatment of patients with HIV-1 infection.
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