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Mol. Nutr. Food Res. 2015, 0,1–13 1
DOI 10.1002/mnfr.201500031
REVIEW
L-Cysteine metabolism and its nutritional implications
Jie Yin1,2∗, Wenkai Ren1,2 ∗, Guan Yang3, Jielin Duan1,2, Xingguo Huang4, Rejun Fang4,
Chongyong Li1, Tiejun Li1∗∗, Yulong Yin1,5, Yongqing Hou6, Sung Woo Kim7
and Guoyao Wu1,6,8
1Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of
Agriculture, Hunan Provincial Engineering Research Center of Healthy Livestock, Key Laboratory of
Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of
Sciences, Changsha, Hunan, China
2University of Chinese Academy of Sciences, Beijing, China
3Department of Animal Science, University of Florida, Gainesville, FL, USA
4Department of Animal Science, Hunan Agriculture University, Changsha, China
5School of Life Sciences, Hunan Normal University, Changsha, China
6Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan Polytechnic University,
Wuhan, China
7Department of Animal Science, North Carolina State University, Raleigh, NC, USA
8Department of Animal Science, Texas A&M University, College Station, TX, USA
Received: January 16, 2015
Revised: April 8, 2015
Accepted: April 23, 2015
L-Cysteine is a nutritionally semiessential amino acid and is present mainly in the form of
L-cystine in the extracellular space. With the help of a transport system, extracellular L-cystine
crosses the plasma membrane and is reduced to L-cysteine within cells by thioredoxin and
reduced glutathione (GSH). Intracellular L-cysteine plays an important role in cellular home-
ostasis as a precursor for protein synthesis, and for production of GSH, hydrogen sulfide (H2S),
and taurine. L-Cysteine-dependent synthesis of GSH has been investigated in many patholog-
ical conditions, while the pathway for L-cysteine metabolism to form H2S has received little
attention with regard to prevention and treatment of disease in humans. The main objective of
this review is to highlight the metabolic pathways of L-cysteine catabolism to GSH, H2S, and
taurine, with special emphasis on therapeutic and nutritional use of L-cysteine to improve the
health and well-being of animals and humans.
Keywords:
L-Cysteine / GSH / H2S / Nutritional potential / Taurine
1 Introduction
L-Cysteine is a nutritionally semiessential amino acid. Three
sources contribute to L-cysteine in the body: absorption from
diets, the transsulfuration pathway from L-methionine degra-
dation, and breakdown of endogenous proteins. In food and
tissue proteins and in the blood, L-cysteine exists mainly in
the form of L-cystine because L-cysteine is rapidly oxidized
to L-cystine in normoxic conditions. Inside cells, L-cysteine is
Correspondence: Yulong Yin
E-mail: yinyulong@isa.ac.cn
Abbreviations: 3MP, 3-mercaptopyruvate; ␥-Glu-cys,␥-
glutamylcysteine; CBS, cystathionine -synthase; CDO,cysteine
dioxygenase; CSD, cysteinesulfinate decarboxylase; CSE,cys-
tathionine ␥-lyase; GCL, glutamate cysteine ligase; GS,GSHsyn-
thase; GSH, glutathione; H2S, hydrogen sulfide; PLP, pyridoxal
5-phosphate; Tr x , thioredoxin
the prevailing form due to the highly reducing conditions [1].
Imbalance of extracellular L-cysteine/L-cystine is associated
with oxidative stress and other pathological disorders and
has been reviewed by other researchers [2–4]. Although L-
cysteine and L-cystine metabolism via multiple ways have not
been fully explored in all tissues, results of previous studies
indicate that the balance between extracellular and intracellu-
lar L-cysteine/L-cystine is largely regulated by transportation.
Currently, L-cysteine and L-cystine transport have been shown
to be associated with systems A, ASC, L, Xc−,B
o,+,andX
−AG
(Fig. 1) [1, 5, 6]. For more specific details of the contribution
of these transport systems, readers are referred to the reviews
by Conrad and Sato [1], Aoyama et al. [7], and Kilberg et al.
[8].
∗These authors contributed equally to this study.
∗∗Additional corresponding author: Tiejun Li
E-mail: tjli@isa.ac.cn
Colour online: See the article online to view Fig. 1 in colour.
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2J. Yin et al. Mol. Nutr. Food Res. 2015, 0,1–13
Figure 1. Extracellular and intracellular L-cysteine/L-cystine bal-
ance and L-cysteine/L-cystine transport systems. Glu, L-glutamate;
Cyss, L-cystine; Cys, L-cysteine; GSH, glutathione; Trx, thiore-
doxin.
Efflux of L-cysteine from cells and uptake of L-cystine by
cells improve the intracellular ratio of L-cystine to L-cysteine.
In contrast, uptake of L-cysteine by cells and its oxidation to
L-cystine, and the efflux of L-cystine by cells increase the ex-
tracellular ratio of L-cystine to L-cysteine (Fig. 1). Meanwhile,
in order to satisfy cellular requirements, L-cystine is widely
transported into cells. Intracellular conversion of L-cystine
into L-cysteine has been considered to be a key process to
mediate extracellular L-cysteine/L-cystine redox, as well as the
synthesis of protein and glutathione (GSH) [9]. However, spe-
cific redox systems or enzymes responsible for this reduction
have not been fully identified. Based on the current litera-
ture, at least two related systems are known to catalyze the re-
duction of L-cystine into L-cysteine: thioredoxin-1/thioredoxin
reductase 1 (Trx1/TR1) and glutaredoxin-1/GSH/GSH disul-
fide reductase (Grx1/GSH/GR) [10, 11]. Jones et al. [4] have
modeled reduced (Trx or GSH) or oxidized (reactive oxygen
specious, O2or CySS) redox-related reactions: PrSH +Cys-
tine →PrSS-cysteine +L-cysteine (activity “on” or “off”) and
Pr-SS-cysteine +Trx/GSH →PrSH +CySSG (the oppo-
site to the reaction above). Such network suggests that Trx
and GSH contribute to intracellular conversion of L-cystine
to L-cysteine and the intracellular reducing status, which has
been further confirmed by other lines of evidence. The redox
states of both Trx1 and GSH/oxidized GSH are more re-
ducing than intracellular L-cysteine/L-cystine redox (–160 to
–125 mV), with Trx1 being maintained in the range of –280
to –270 mV and GSH/oxidized GSH being fluctuated from
–250 mV in rapidly proliferating cells to –200 mV in differ-
entiated cells [3,12,13]. These data reveal the high capacity of
Trx and GSH for L-cystine reduction. The rate of intracellular
conversion of L-cystine to L-cysteine has been estimated to
be approximately 2 M/min in cells with 3 mM GSH and
30 ML-cystine, while the value may be catalytically reached
to about 7 M/min with the help of Grx or Trx [4, 14].
The metabolic pathways of intracellular L-cysteine include
protein synthesis, as well as the generation of GSH (␥-
glutamyl-cysteinyl-glycine), hydrogen sulfide (H2S), cysteine-
sulfinate, taurine, pyruvate, and inorganic sulfur (Fig. 2) [15].
Figure 2. Intracellular cysteine metabolism. Hcy, homocysteine;
Cysta, cystathionine; Cys, L-cysteine; L-Ser, serine; Cyss, L-cystine;
␥-Glu-cys, ␥-glutamylcysteine; GSH, glutathione; CSA, cysteine-
sulfinate; CBS, cystathionine -synthase; CSE, cystathionine ␥-
lyase; CDO, cysteine dioxygenase; CSD, cysteinesulfinate decar-
boxylase; 1, GSH/Trx systems; 2, GCL (glutamate cysteine ligase);
3, GS (GSH synthase); 4, aspartate (cysteinesulfinate) aminotrans-
ferase.
L-Cysteine can regulate nutrient metabolism, oxidative stress,
physiologic signaling pathways, and associated diseases via
the production of GSH, H2S, and taurine. This review high-
lights the metabolic pathways of L-cysteine catabolism to
GSH, H2S, and taurine, with special emphasis on therapeutic
and nutritional use of L-cysteine to improve the health and
well-being of animals and humans.
2L-Cysteine/GSH system
Apart from protein synthesis, L-cysteine mainly serves as
a precursor for GSH along with L-glutamate and glycine.
GSH is synthesized de novo in two successive enzymatic
ATP-dependent reactions. First, L-cysteine and L-glutamate
are coupled to form the dipeptide ␥-glutamylcysteine (␥-Glu-
cys), with the reaction being catalyzed by glutamate cysteine
ligase (GCL). Then, GSH synthase (GS) converts ␥-Glu-cys
and glycine to GSH [16, 17]. However, the main sources of
the GSH precursors have not been quantified. Thus, we
have evaluated the combined coefficients using an orthog-
onal array design in the liver of mice receiving dietary sup-
plementation with L-cysteine, glycine, and L-glutamate (Table
1A). The results showed that supplementation with L-cysteine
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Mol. Nutr. Food Res. 2015, 0,1–13 3
Ta b l e 1 . Liver GSH concentrations in mice receiving dietary supplementation with L-cysteine, L-glutamate, and glycine for 7 days
A
Groups Dietary supplementation GSH concentration
(mmol/L)a)
L-Cysteine L-Glutamate Glycine
1 0.0% 0.0% 0.0% 5.29 ±1.02
2 0.0% 0.5% 0.5% 3.58 ±1.46
3 0.0% 1.0% 1.0% 3.88 ±1.70
4 0.5% 0.0% 0.5% 5.90 ±0.65
5 0.5% 0.5% 1.0% 4.39 ±1.09
6 0.5% 1.0% 0.0% 6.39 ±0.50
7 1.0% 0.0% 1.0% 5.03 ±1.79
8 1.0% 0.5% 0.0% 4.86 ±1.36
9 1.0% 1.0% 0.5% 4.63 ±1.40
B
SSc) MSd) p-ValueDietary
supplementation
GSH concentration (mmol/L)
0.0%b) 0.5%b) 1.0%b)
L-Cysteine 4.48B5.61A4.81B22.37 6.57 0.002
L-Glutamate 5.47A4.19B4.93AB 23.48 6.90 0.002
Glycine 4.92 4.92 4.90 0.50 0.15 0.864
Values are means ±SD, n=10. Ninety male ICR mice (with an average body weight of 26 g) were randomly divided into one of nine groups
(n=10/group). Mice received dietary supplementation with L-cysteine, L-glutamate, or glycine or their combinations. The composition of
the basal diet was the same as previously reported [108]. At the end of the 7-day supplementation period, liver samples were harvested
and homogenized (1 g tissue in 9 mL saline) for GSH determination using an ELISA kit (Nanjing Jiancheng Bio. Institute, China).
a) Values are expressed as Mean ±SD.
b) Dietary dosage of amino acids.
c) Type II sum of squares.
d) Mean square; orthogonal analysis was subjected to general linear models. Multiple tests were performed using the Tukey’s multiple
comparisons test (IBM SPSS Statistic 20). Means in the same row with different superscripts are different (p<0.05).
and L-glutamate increases hepatic GSH synthesis (Table 1B).
Furthermore, we found that supplementation with an
appropriate dose of L-cysteine improves GSH synthesis, while
excessive dietary L-cysteine reduces liver GSH concentration
(Table 1B).
2.1 GCL
Chen et al. have reported that several factors can affect GSH
synthesis, including the amount of GCL, the availability of
L-cysteine, and the extent of feedback inhibition of GCL by
GSH [16]. Among these factors, GCL is a rate-controlling step
and plays a critical role in L-cysteine metabolism and GSH
synthesis. The eukaryotic GCL consists of a 73-kDa catalytic
subunit (GCLC) and a 31-kDa modifier subunit (GCLM), each
of which is encoded by separate genes and exhibits different
function in ␥-Glu-cys synthesis [18]. GCLC contains binding
sites for L-glutamate, L-cysteine, and ATP and is responsible
for all the catalytic activity of GCL [19]. In contrast, GCLM has
a regulatory function affecting the affinity of the holoenzyme
for glutamate and GSH [20]. Of note, feedback inhibition by
GSH involves reduction of the enzyme and also competition
between GSH and glutamate for the glutamate-binding site
[19, 20]. Currently, two models of GCL activation are widely
cited in the GCL-related literature. The first model holds that
the GCL holoenzyme is predominantly sequestered in the
cytosol as an inactive heterodimer, which can be oxidized
to its activated state by formation of a disulfide bridge be-
tween GCLC and GCLM [18]. The activated GCL holoenzyme
substantially improves the efficiency of ␥-Glu-cys synthesis.
Another model indicates that the active status of GCL de-
pends on a dynamic equilibrium between monomeric and
holoenzyme forms of the enzyme [18]. The shift of GCL to
the high activity pool involves a change in GCLC, such that
an N-terminal GCLC epitope associated with enzyme activity
is protected in extracts with high GCL activity. Likewise, in-
creased formation of high activity heterodimeric complexes
results in a shift to more efficient GSH production [18].
2.2 GS
In eukaryotes, GS is a homodimeric enzyme with two
identical subunits to catalyze the condensation of ␥-Glu-cys
and glycine to form GSH [21]. Currently, GS has received
relatively little attention in GSH biosynthesis, because GCL
is considered to be the rate-limiting step and GS is not
subject to feedback regulation by excessive GSH. However,
we found that dietary supplementation with L-cysteine
showed a dosage-dependent inhibitory effect on GS activity
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4J. Yin et al. Mol. Nutr. Food Res. 2015, 0,1–13
Figure 3. The response of liver GS activity to dietary L-cysteine in
adult mice. The experimental detail is given in Table 1. Hepatic GS
activity was measured using an ELISA kit (Nanjing Jiancheng Bio.
Institute, China). Results were analyzed by one-way analysis of
variance. Comparison of means was performed using the Tukey’s
multiple test (INM SPSS Statistic 2.0). Values are expressed as
mean ±SD. Means in the same row with different superscripts
are different (p<0.05).
in the liver of mice (Fig. 3), while L-glutamate and glycine
failed to affect GS activity (unpublished data), indicating that
supplementation with an appropriate dose of L-cysteine
maintains a higher GS activity while excessive L-cysteine
inhibits GS activity. Physiological abundance and activity
of GS also play a key role in GSH synthesis and L-cysteine
homoeostasis. For example, decreased GS activity occurs
in response to the depletion of the GSH pool under many
pathological conditions, including surgical trauma [22]. GS
deficiency can lead to the accumulation of ␥-Glu-cys in cells,
and this metabolite is further converted to 5-oxoproline.
5-Oxoproline is associated with severe metabolic acidosis,
hemolytic anemia, and damage to the central nervous system
[23, 24]. In support of this view, increased expression of
GS by all-trans retinoic acid (which has no effect on GCL
abundance) has been shown to enhance GSH synthesis in
myeloid-derived suppressor cells [25].
3L-Cysteine and H2S synthesis
H2S, nitric oxide, and carbon monoxide are the three gaseous
signaling molecules that have received considerable atten-
tion from biological scientists in recent years. These three
gasotransmitters perform a variety of homeostatic functions
[26]. Endogenous H2S is an anti-inflammatory, antioxidant,
and neuroprotective agent. Many diseases, including neuro-
logical diseases, cardiovascular diseases, inflammation, and
metabolic disorders, have been linked to metabolic disorders
of endogenous H2S [27–29]. The therapeutic administration
of H2S donors appears relevant in the treatment of various
diseases. L-Cysteine is the preferred substrate for H2Sgen-
eration and accounts for 70% of the gas produced under
normal conditions [30]. Meanwhile, a novel source of H2S
generation from D-cysteine has been observed in recent years,
and this metabolic pathway has been considered to be more
effective than L-cysteine in neuroprotection against oxidative
stress and ischemia-reperfusion injury [31].
3.1 H2S production from L-cysteine
L-Cysteine-mediated generation of endogenous H2Siscat-
alyzed by two pyridoxal 5-phosphate (PLP) dependent en-
zyme systems, including cystathionine -synthase (CBS)
and cystathionine ␥-lyase (CSE) and PLP-independent mer-
captopyruvate sulfurtransferase (MST) along with L-cysteine
aminotransferase [32, 33]. CBS mainly catalyzes the -
replacement of the hydroxyl group of serine with homocys-
teine and then forms cystathionine with the release of H2O
[34]. L-Cysteine is structurally similar to serine with an OH
group replaced by an SH. Thus, CBS can also use L-cysteine
as a substrate to form cystathionine with the release of H2S
under pathological situations involving oxidative injury [34].
CBS has been demonstrated to be a major contributor for
the production of H2S. It is a highly regulated enzyme. S-
adenosylmethionine serves as its allosteric activator and plays
an important role in regulating its activity and concentration
[35]. Stipanuk et al. [32] reported that an increase in CBS activ-
ity by supplementation with S-adenosylmethionine markedly
promotes H2S production by about 50% in both liver and
kidney [32], while addition of amino-oxyacetate, a CBS in-
hibitor, blocks H2S production and deteriorates oxidative in-
jury [36]. Consequently, CBS knockout mice exhibit severe
accumulation of homocysteine, as well as an inhibition of the
-replacement reactions involving both serine and L-cysteine
[34].
However, Shibuya et al. [37] reported that brain ho-
mogenates of CBS knockout mice, even in the absence of
PLP, produced H2S at levels similar to those of wild-type
mice, suggesting the presence of another H2S-producing en-
zyme. Indeed, CSE has been reported to be the major al-
ternative reaction for H2S production. In addition to cat-
alyzing the catabolism of cystathionine to form L-cysteine,
CSE can directly facilitate the conversion of L-cysteine into
L-serine and H2Svia␣,elimination [34, 38]. Furthermore,
CSE participates in the disulfide elimination reaction to pro-
duce pyruvate, ammonia, and thiocysteine. Thiocysteine re-
acts with a thiol group in such substances as L-cysteine to
generate H2S [34]. Previous reports have estimated that CSE
contributes to about 70% of the total H2S generation under
the normal conditions [38]. Treatment with propargylglycine,
a CSE inhibitor, significantly suppresses sulfur anion pro-
duction and L-cysteine metabolism by about 50% in rat renal
cortical tubules [39]. The H2S-producing activity of CSE is
negatively regulated by cellular Ca2+concentration. CSE effi-
ciently produces H2S at steady-state low Ca2+concentrations,
but this reaction is suppressed at high Ca2+concentrations
in the presence of PLP [40]. Thus, physiological calcium lev-
els may control CSE-mediated H2S formation. Emerging ev-
idence has shown that a genetic deficiency of CSE results
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Mol. Nutr. Food Res. 2015, 0,1–13 5
in marked reductions in H2S concentrations in the serum,
heart, aorta, and other tissues in mice [41], leading to ex-
acerbated myocardial ischemia/reperfusion injury, impaired
cardiac mitochondrial function, and oxidative stress [42, 43].
Upregulation of the CSE/H2S pathway provides various ther-
apeutic avenues, including rescuing impaired arteriogenesis
in mouse hind limb ischemia [44], improving TNF-induced
insulin resistance associated with obesity and type 2 diabetes
[45], and modulating central neurotransmitter input [46].
In the MST-mediated pathway for H2S genera-
tion, L-cysteine firstly undergoes transamination with a-
ketoglutarate to form 3-mercaptopyruvate (3MP). CAT (a PLP-
dependent enzyme) is responsible for this reaction [47]. 3MP
is then covalently linked via a disulfide bond to the active-site
cysteine residue of MST to generate H2S [37, 48]. MST also
produces H2S form thiosulfate, and several reducing sub-
stances, such as Trx and dihydrolipoic acid, are likely to be
the major physiological persulfide acceptors and can facili-
tate H2S release from MST [49,50]. The MST/H2S pathway is
susceptible to oxidative stress, and treatment of H2O2inhibits
MST activity and interferes with the positive bioenergetic role
of the 3MP/MST/H2S pathway in vitro [51]. The MST/H2S
pathway may also be involved in the regulation of respiration
and protection in cells [52].
Although the contribution of MST versus the other two
H2S generators, CBS and CSE, has been difficult to evaluate
because of varied reaction conditions, we may make con-
clusions that the CBS-mediated H2S production mainly oc-
curs under pathological conditions involving oxidative stress,
while the CSE-catalyzed H2S formation largely contributes to
normal H2S metabolism. CBS and CSE are more likely to be
potential therapeutic targets than MST for H2Sproductionas
MST may not be responsible for the increased production of
H2S in various conditions [53].
3.2 H2S production from D-cysteine
More recently, Shibuya et al. [31, 33] found an additional
biosynthetic pathway for the production of H2SfromD-
cysteine involving MST and D-amino acid oxidase (DAO). D-
cysteine is derived from L-cysteine in food via racemization by
heat and alkaline treatment during food processing [54]. The
pathway for producing H2SfromD-cysteine is different from
that from L-cysteine. The differences include the optimal pH,
the dependency on PLP, and the stability against the freezing-
thawing procedure [33]. Unlike the L-cysteine/H2S pathway,
in which the responsible enzymes are expressed in many tis-
sues [32, 55, 56], D-cysteine-mediated H2S generation occurs
predominantly in the cerebellum and the kidney, as D-amino
acid oxidase is mainly expressed in astrocytes, glia, and sev-
eral types of neurons including the Golgi and Purkinje cells
[31, 57]. Furthermore, there are no enzymes associated with
D-cysteine metabolism, and D-cysteine has been widely hy-
pothesized to produce H2S directly via chemical degradation.
4 Hypotaurine and taurine
Several reports have indicated that an increase in L-cysteine
availability as a result of the consumption of a sulfur amino
acid rich diet can rapidly activates L-cysteine dioxygenase
(CDO) [58], which catalyzes the oxidation of the L-cysteine
thiol group to form cysteinesulfinate, which is also called cys-
teine sulfinic acid or 3-sulfinoalanine [34]. Cysteinesulfinate
is a major precursor of taurine, and this metabolic pathway
is involved in the decarboxylation and oxidation of cysteine-
sulfinate by cysteinesulfinate decarboxylase (CSD; Fig. 2).
4.1 CDO-mediated taurine formation
CDO is a highly regulated enzyme and widely expressed
in hepatocytes, adipocytes, exocrine cells, goblet cells, and
tubular epithelial [34]. Under conditions of a low intracellu-
lar concentration of L-cysteine, CDO activity is blocked via
ubiquitination by 26S proteasome [59], while elevated levels
of L-cysteine can rapidly increase hepatic or adipocyte CDO
activity by up to 45- or tenfold, respectively [34]. For example,
CDO activity increased with an increase in dietary protein
levels, and the higher enzyme activity was paralleled by a
greater rate of the production of taurine plus hypotaurine
plus sulfate from L-cysteine [60]. Thus, CDO may serve as a
major regulatory factor in intracellular L-cysteine levels and
taurine formation. Previous studies with cell culture systems
have shown that L-cysteine deprivation induces CDO ubiq-
uitination, while addition of lactacystin or proteasome in-
hibitor 1 (PS1, N-carboxybenzyl-IleGlu[OtBu]AlaLeu-CHO),
the 26S proteasome inhibitor, markedly blocks intracellular
CDO degradation in L-cysteine-deficient cells [34, 61]. Stud-
ies in vivo have further indicated the switch of CDO activity
in response to changes in intracellular L-cysteine levels. For
example, feeding a L-cysteine-rich diet (100 g casein +8.1 g
L-cysteine/kg) or a high protein diet (400 g casein) resulted in
a significant increase in hepatic CDO concentrations and a
decrease in ubiquitinated forms of the CDO pool. Addition-
ally, inhibition of 26S proteasome by PS1 stabilized hepatic
CDO in rats fed a low protein diet [59,62,63]. Metabolic anal-
ysis has indicated that the increased CDO activity promotes
L-cysteine metabolism toward hypotaurine and taurine pro-
duction in that hepatic hypotaurine level was about 37 nmol/g
in rats fed a low protein diet, but increased to 680 nmol/g at
3.5 h after the injection with PS1 [61]. Furthermore, primary
hepatocytes from mice lacking CDO showed increases in L-
cysteine concentrations and higher rates of metabolism of
L-cysteine to H2S and thiosulfate [64]. Thus, CDO sensitively
responds to a high intracellular concentration of L-cysteine
and plays an important role in the production of hypotaurine
and taurine.
Previous studies have extensively addressed the role of
CDO in L-cysteine metabolism and other neurological disor-
ders [64–66], but the regulatory mechanism for the effect of
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6J. Yin et al. Mol. Nutr. Food Res. 2015, 0,1–13
Ta b l e 2 . Summary of effects of dietary cysteine or its precursors in different pathological conditions
Risk factor Supplementary
conditions
Response Reference
HIV infection L-Cysteine and
L-glutamine or glycine
Taurine and GSH levels ↑, insulin sensitivity↑[83, 109]
Aging L-Cysteine and glycine;
N-acetylcysteine
GSH levels ↑, oxidative stress ↓, proinflammatory state↓[110, 111]
Type-2 diabetes L-Cysteine or
N-acetylcysteine
GSH levels ↑; the insulin-dependent signaling cascades
of glucose metabolism↑; blood glucose, glycated
hemoglobin, NF-kappaB activation↓
[112–115]
Cardiovascular
disease
N-acetylcysteine Proinflammatory cytokines↓, antioxidative capacity↑,
energy metabolism↑
[116]
Inflammatory bowel
disease
L-Cysteine Proinflammatory cytokines↓, apoptosis↓[117]
Nonalcoholic
steatohepatitis
patients
L-Cysteine-rich whey
protein
GSH levels ↑, hepatic macrovesicular steatosis↓[118]
Smoking N-acetylcysteine GSH levels ↑[119]
Alzheimer’s disease N-acetylcysteine Cognitive functioning↑, AD neuropathology↓[120]
L-methionine
deficiency
L-Cysteine Plasma homocysteine concentration↓[121]
Gastric cancer S-propargyl-cysteine H2S production↑, tumor weights, and tumor volumes↓[122]
↑, increase; ↓, decrease.
L-cysteine on CDO ubiquitination has not been fully explored.
Stipanuk’s group has investigated a substrate turnover de-
pendent formation of a thioether cross-link between the sul-
fur of residue Cys93 and the aromatic side chain of residue
Tyr157 in CDO [34]. Their results indicated that the imma-
ture CDO and inactive mutant forms of CDO fail to form
any cross-link and exhibit low enzymatic activity and that a
high catalytic efficiency can be achieved by the formation of
Cys-Tyr cofactors. More recently, Goldberg’s and Gao’s group
have reported structural and functional models for the active
site of CDO [66, 67]. Formation of a CDO-Cys-Tyr cross-link
requires a transition metal cofactor (ferrous iron [Fe2+]and
oxygen [O2]). It is speculated that the valence change of the
Fe center makes the Cys-bound complexes effectively catalyze
the oxidation of L-cysteine, as the ferric-superoxo species is an
active oxidant and exhibits high reactivity in such a reaction.
4.2 CSD-mediated taurine formation
The cysteinesulfinate produced by CDO can be further metab-
olized by CSD to hypotaurine, which is subsequently oxidized
to taurine. Transamination is another metabolic pathway for
cysteinesulfinate to form pyruvate and sulfite by aspartate
(cysteinesulfinate) aminotransferase. A previous report has
estimated that 66 and 34% cysteinesulfinate participates in
taurine and sulfite production, respectively [34]. The preferred
metabolic pathway of cysteinesulfinate is likely dependent on
the abundance of the enzymes and their affinities for their
substrates. Although there is little information about intra-
cellular concentrations of the enzymes, compelling evidence
has shown that high levels of CSD in liver and adipose tissue
contributes to a higher capacity for taurine synthesis [68,69].
Studies on kinetics of these enzymes have revealed that CSD
has a higher affinity for cysteinesulfinate as the Kmin taurine
synthesis for cysteinesulfinate is 0.04 – 0.17 mM, while the
value is 3 – 25 mM for aspartate aminotransferase [34].
However, the L-cysteine/taurine pathway can be limited at
high protein levels due to the decrease in CSD activity such
that sulfate production from cysteinesulfinate is favored [60].
5 Nutritional use of L-cysteine
The balance between L-cysteine and L-cystine plays a vital
role in controlling redox potential, synthesis of other active
substrates (i.e., GSH, H2S, and taurine), oxidative stress,
and inflammatory response [3, 4, 70]. Dietary intake of
sulfur amino acids affects cell signaling via modulating
intracellular concentrations of L-cysteine and L-cystine, as
well as L-cysteine/L-cystine redox state in the postprandial
period [71]. Thus, recent years have witnessed growing
interest in the use of L-cysteine for improving health in
animals and humans (Table 2).
5.1 Oxidative stress
We found that various kinds of stress can lead to oxida-
tive injury in animals [72–74]. Additionally, oxidative stress
is thought to be involved in the development of many
diseases or may exacerbate their symptoms [75]. GSH is
the most abundant cellular thiol antioxidant and plays a
C2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mnf-journal.com
Mol. Nutr. Food Res. 2015, 0,1–13 7
protective role against toxicity arising from excessive amounts
of endogenous and exogenous electrophiles [16] via scaveng-
ing hydroxyl radical and superoxide directly, and serving as
a cofactor for the enzyme GSH peroxidase (GPx) in me-
tabolizing H2O2and lipid peroxides. Thus, current reports
mainly focused on the positive effects of L-cysteine in dif-
ferent pathological conditions via increasing GSH synthesis
and suppressing oxidative stress or inflammatory response,
while these reports failed to recognize other beneficial effects
of dietary L-cysteine in the production of H2S and taurine.
Increases in endogenous H2S generation by CBS and CSE
contribute to some pathological conditions [76]. Lu et al. [36]
also demonstrated that H2S has potential therapeutic value
for oxidative stress-induced brain damage via a mechanism
involving enhanced L-glutamate uptake. Oxidative stress can
impact the function of L-glutamate transporters [77] and result
in L-glutamate accumulation in the synaptic cleft, which fur-
ther leads to toxicity and neural injury via overactivation of re-
lated receptors. Thus, dysfunction of L-glutamate transporters
is commonly associated with neurodegenerative diseases and
some acute brain injuries [78]. In addition, L-glutamate is an
inhibitor of the Xc−system, which transports one molecule
of L-cystine into cells and, therefore, releases one molecule of
glutamate into the extracellular space [1]. The excessive extra-
cellular glutamate plays a feedback inhibitory role in L-cystine
influx and, therefore, L-glutamate neurotoxicity is primarily
characterized by the depletion of cellular GSH [79]. In vitro
studies have reported that addition of NaHS (an H2S donor)
reverses H2O2-impaired L-glutamate transport and enhances
GSH production [36]. This pathway may be another important
factor contributing to the pathogenesis of brain and neural
diseases.
Taurine is an organic osmolyte involved in modulation of
intracellular free calcium concentration and has been con-
sidered as one of the most essential substances in the body
due to: (i) its broad distribution, cytoprotective effects, an-
tioxidative properties; (ii) its role in regulating intracellular
Ca2+concentration, movement of ions and neurotransmit-
ters, proinflammatory response; and (iii) its functional sig-
nificance in cell development, nutrition, and survival [80,81].
Recently, several reports have shown that taurine serves as
a protective agent against several environmental toxins and
drug-induced organ dysfunction and diabetes [82]. Thus, an
increase in the conversion of L-cysteine to taurine provides
a novel insight into L-cysteine nutrition and its therapeutic
potential. For example, dietary N-acetylcysteine (a stable and
water-soluble precursor of L-cysteine) significantly increased
the plasma levels of taurine and GSH in patients with the
human immunodeficiency virus (HIV) [83].
5.2 Gut function
Gut plays important roles in secretions, food digestion, nu-
trient absorption and metabolism, and cross-talk with the in-
testinal microbiota. Gut mucosal proteins and mucins, which
contribute to intestinal integrity, are rich in L-cysteine [84].
Compelling evidence from in vivo studies has shown that
L-cysteine plays key roles in maintaining intestinal struc-
ture and function [84, 85]. Bauchart-Thevret et al. [86] eval-
uated first-pass splanchnic metabolism of dietary L-cysteine
in weanling pigs and found that gastrointestinal tract utilizes
25% of the dietary L-cysteine intake and that synthesis of
mucosal epithelial proteins, such as GSH and mucins, is a
major nonoxidative metabolic fate for L-cysteine. Thus, we can
speculate that L-cysteine deficiency contributes significantly
to the intestinal mucosal atrophy and reduced secretion of
mucins [84]. Furthermore, Badaloo et al. [84] reported that
children with malnutrition exhibited gut mucosal atrophy
and depletion of mucins, produced less L-cysteine, and had
a greater requirement for dietary L-cysteine during early and
mid-nutritional rehabilitation. Thus, L-cysteine serves as an
essential substrate for maintaining gut function.
5.3 Lipid metabolism
Dietary supplementation with L-cysteine can improve lipid
metabolism. Elshorbagy et al. [87] reported that total L-
cysteine concentration in serum was positively correlated
with fat mass. Indeed, the correlation was stronger with to-
tal L-cysteine than with serum lipids such as triglycerides
[87]. Triglycerides are formed by combining glycerol with
three fatty acid molecules and play a critical role in lipid
metabolic network as energy sources and transporters of di-
etary fat. In humans and animals, high plasma concentrations
of triglycerides are associated with various diseases, including
atherosclerosis, heart disease, and stroke [88]. Lee et al. [89]
reported that L-cysteine effectively reduces triglyceride con-
centrations in serum and liver in a dose-dependent manner
in rats fed a normal diet [89]. The derivatives of L-cysteine also
regulate lipid metabolism. For example, S-methyl L-cysteine, a
hydrophilic L-cysteine-containing compound, exhibits hypo-
glycemic and antihyperlipidemic properties through reduc-
tion in fasting plasma levels of glucose, total cholesterol,
triglycerides, LDL cholesterol in fructose-induced diabetic
rats [90]. N-acetylcysteine also has been demonstrated to im-
prove lipid metabolism through affecting serum cholesterol,
triglycerides, VLDL, and HDL levels [91]. Although little is
known about the underlying mechanisms, some reports in-
dicate (i) supplementation with L-cysteine targets at gene ex-
pression of the sterol response element-binding protein, fatty
acid synthase, and stearoryl-coenzymeA desaturase-1 [92]; (ii)
reduced oxidation of L-cysteine to form taurine leads to a defi-
ciency of taurine [87,93] and abnormal lipid metabolism [94].
5.4 Growth
Previous reports have indicated that dietary supplementation
with L-cysteine affects animal growth performance, including
food intake, body weight gain, and feed efficiency. However,
the effect of L-cysteine on growth performance is not always
C2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mnf-journal.com
8J. Yin et al. Mol. Nutr. Food Res. 2015, 0,1–13
Ta b l e 3 . Effects of dietary L-cysteine on growth performance in
rats
Health status Dosage Weight
gain
Food
intake
Reference
Healthy 1–2% diet ↓↓[89]
Healthy 1–4 mmol/kg - ↓[95]
Aging 6.8 g/kg N ↑[123]
Sucrose
stress
5.5–16 g/kg N N [115]
Diabetes 1 mg/kg N - [114]
L-methionine-
restricted
diet
0.5% ↑N [124]
N, no effect; ↑, increase; ↓, decrease.
detected depending on experimental design (Table 3). Mc-
Gavigan et al. [95] reported that a low dosage of L-cysteine
(oral gavage: 4 mmol/kg) is more anorectic than L-arginine
and L-lysine [95], high dosages of which can inhibit feed in-
take [96]. Lee et al. [89] further investigated the anorectic effect
of L-cysteine and found that dietary supplementation with L-
cysteine effectively reduces final body weight, body weight
gain, food intake, and feed efficiency in rats [89]. We noted
that animals in these studies were either aging ones or in a
catabolic state, while an anorectic effect appeared in young
and healthy animals (Table 3). Collectively, these studies sug-
gest that the anorectic effect of L-cysteine depends on the
health status, nutritional level, and age of the animals. Un-
der normal conditions, supplementation with L-cysteine may
reduce feed intake and weight gain in young animals.
L-Cysteine confers a bitter taste, which can contribute to
its inhibitory effect on feed intake [89, 97]. This explanation
is not convincing, as a latest report showed that intraperi-
toneal administration of 2 mmol/kg also reduces feed intake
in rats [95]. McGavigan et al. [96] further investigated the
mechanism for L-cysteine to reduce feed intake and found
that L-cysteine activates promiscuous amino acid sensing re-
ceptors, such as T1R1/T1R3, CaSR, and GPRC6A [96]. How-
ever, these receptors may not mediate the effects of L-cysteine
on appetite, as other amino acids (i.e., L-serine, L-threonine,
and L-histidine) also induce a strong T1R1/T1R3-, CaSR-,
and GPRC6A-mediated response [98] but do not inhibit food
intake or growth performance of the animals [95]. More re-
cently, acyl ghrelin has been suggested to play a decisive role
in L-cysteine-mediated appetite stimulation, as a reduction
in the circulating level of acyl ghrelin occurred in both ro-
dents and humans receiving dietary supplementation with
L-cysteine [95]. Meanwhile, the anorectic effect of L-cysteine
is attenuated in transgenic mice overexpressing ghrelin [95].
5.5 Effects of supplemental L-methionine as a
L-cysteine precursor
L-methionine is the physiological precursor of endogenous
L-cysteine [99]. Thus, the metabolism and availability of
L-methionine can affect the nutritional efficacy of dietary L-
cysteine in animals [100, 101]. L-methionine can replace L-
cysteine in diets to maintain normal protein synthesis and
normal growth in animals, but not vice versa [102]. However,
L-cysteine can spare L-methionine in animals. Thus, supple-
menting L-cysteine to a L-methionine-restricted diet reverses
the adverse effects of L-methionine deficiency [103, 104]. Sev-
eral studies have concluded that when the diet contains both
L-methionine and L-cysteine, the mean requirements of L-
methionine and L-cysteine by infants are 38 and 91 mg
kg−1day−1L-cysteine, respectively [106]. The values for adult
men are 12.6 and 21 mg kg−1day−1for L-methionine and
L-cysteine, respectively [102].
The ability of dietary L-methionine to supply endogenous
L-cysteine has been studied in edematous severe acute malnu-
trition. In this case, L-methionine supplementation increases
L-cysteine production but has no effect on GSH synthesis
[105]. One explanation is that the conversion of L-methionine
to L-cysteine in the liver is insufficient for sustaining GSH
production. This necessitates dietary supplementation with
L-cysteine to partially fulfill the demand for this amino acid in
edematous severe acute malnutrition [105]. Effects of dietary
supplementation with L-cysteine or its precursors on animals
under different pathological conditions [106–124] are sum-
marized in Tables 2 and 3. Taken together, these findings
indicate that direct provision of L-cysteine in diets is required
under conditions of impaired L-methionine catabolism so as
to maintain whole-body protein synthesis and physiological
homeostasis.
6 Conclusion and perspectives
L-Cysteine is not only a building block of protein, but is also
a regulator of cell signaling pathways. Therefore, L-cysteine
is now classified as a functional amino acid in nutrition
[125]. There is a complex relationship between L-methionine
and L-cysteine in their metabolism and nutrition such that
dietary L-methionine is not always effective in supplying
endogenous L-cysteine [126]. Under certain conditions when
the absorption or catabolism of L-methionine is impaired, it
is necessary to include L-cysteine in diets so as to maintain
adequate protein synthesis in tissues and whole-body
physiological homeostasis [127, 128]. Dietary L-cysteine sup-
plementation can increase the synthesis of GSH, H2S, and
taurine in animals and humans [126–129]. However, the use
of L-cysteine supplementation as a nutritional intervention of
disease is limited. Emerging evidence shows a positive role
of L-cysteine-rich meals in several pathological conditions, in-
cluding oxidative stress, HIV infection, aging, type-2 diabetes,
and neurodegenerative diseases. In addition, dietary supple-
mentation with L-cysteine or its precursor N-acetyl-cysteine
can improve gut function, growth, and health [128–132].
Future research should focus on: (i) optimal requirements of
L-cysteine by animals and humans fed enteral or parenteral
diets, (ii) nutritional regulation of GSH, H2S, and taurine
C2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mnf-journal.com
Mol. Nutr. Food Res. 2015, 0,1–13 9
synthesis in a cell- and tissue-specific manner, and (iii)
roles of these metabolites to treat and prevent metabolic
disorders. Additionally, caution must be exercised to avoid
high dosages of L-cysteine supplementation in animals and
humans, because L-cysteine exerts an N-methyl-D-aspartate
receptor-mediated excitatory effect in the nervous system. A
previous study indicated that a toxic dosage of intravenous ad-
ministration of L-cysteine for 28 days was 1 g/kg body weight
per day in adult male rats [107]. A toxic dosage of oral admin-
istration of L-cysteine remains to be determined for animals.
This study was supported by the National Natural Science
Foundation of China (nos. 31272463, 31372319, 31402084,
31330075, 31110103909), Hunan Provincial Natural Sci-
ence Foundation of China (no. 12JJ2014), the Hubei Provin-
cial Key Project for Scientific and Technical Innovation (no.
2014ABA022), the Hubei Hundred Talent Program, and Texas
A&M AgriLife Research (H-8200).
The authors have declared no conflict of interest.
7 References
[1] Conrad, M., Sato, H., The oxidative stress-inducible cys-
tine/glutamate antiporter, system x (c) (−): cystine supplier
and beyond. Amino Acids 2012, 42, 231–246.
[2] Kumar, P., Maurya, P. K., L-Cysteine efflux in erythrocytes
as a function of human age: correlation with reduced glu-
tathione and total anti-oxidant potential. Rejuvenation Res.
2013, 16, 179–184.
[3] Go, Y. M., Jones, D. P., Cysteine/cystine redox signaling
in cardiovascular disease. Free Radic. Biol. Med. 2011, 50,
495–509.
[4] Jones, D. P., Go, Y. M., Anderson, C. L., Ziegler, T. R. et al.,
Cysteine/cystine couple is a newly recognized node in the
circuitry for biologic redox signaling and control. FASEB J .
2004, 18, 1246–1248.
[5] Lim, J. C., Lam, L., Li, B., Donaldson, P. J., Molecular identi-
fication and cellular localization of a potential transport sys-
tem involved in cystine/cysteine uptake in human lenses.
Exp. Eye Res. 2013, 116, 219–226.
[6] King, N., Lin, H., Suleiman, M. S., Oxidative stress increases
SNAT1 expression and stimulates cysteine uptake in
freshly isolated rat cardiomyocytes. Amino Acids 2011, 40,
517–526.
[7] Aoyama, K., Watabe, M., Nakaki, T., Modulation of neuronal
glutathione synthesis by EAAC1 and its interacting protein
GTRAP3-18. Amino Acids 2012, 42, 163–169.
[8] Kilberg, M. S., Christensen, H. N., Handlogten, M. E., Cys-
teine as a system-specific substrate for transport system
ASC in rat hepatocytes. Biochem. Biophys. Res. Commun.
1979, 88, 744–751.
[9] Park, Y., Ziegler, T. R., Gletsu-Miller, N., Liang, Y. L. et al.,
Postprandial cysteine/cystine redox potential in human
plasma varies with meal content of sulfur amino acids. J.
Nutr. 2010, 140, 760–765.
[10] Song, J. Y., Roe, J. H., The role and regulation of trx1, a cy-
tosolic thioredoxin in Schizosaccharomyces pombe. J. Mi-
crobiol. 2008, 46, 408–414.
[11] Pai, H. V., Starke, D. W., Lesnefsky, E. J., Hoppel, C. L.
et al., What is the functional significance of the unique
location of glutaredoxin 1 (GRx1) in the intermembrane
space of mitochondria? Antioxid. Redox Signal. 2007, 9,
2027–2033.
[12] Watson, W. H., Pohl, J., Montfort, W. R., Stuchlik, O. et al.,
Redox potential of human thioredoxin 1 and identification
of a second dithiol/disulfide motif. J. Biol. Chem. 2003, 278,
33408–33415.
[13] Khazim, K., Giustarini, D., Rossi, R., Verkaik, D. et al., Glu-
tathione redox potential is low and glutathionylated and
cysteinylated hemoglobin levels are elevated in mainte-
nance hemodialysis patients. Transl. Res. 2013, 162, 16–25.
[14] Sellin, S., Mannervik, B., Reversal of the reaction catalyzed
by glyoxalase I. Calculation of the equilibrium constant for
the enzymatic reaction. J. Biol. Chem. 1983, 258, 8872–8875.
[15] Cresenzi, C. L., Lee, J. I., Stipanuk, M. H., Cysteine is the
metabolic signal responsible for dietary regulation of hep-
atic cysteine dioxygenase and glutamate cysteine ligase in
intact rats. J. Nutr. 2003, 133, 2697–2702.
[16] Chen, Y., Dong, H., Thompson, D. C., Shertzer, H. G. et al.,
Glutathione defense mechanism in liver injury: insights
from animal models. Food Chem. Toxicol. 2013, 60, 38–44.
[17] Ribas, V., Garcia-Ruiz, C., Fernandez-Checa, J. C., Glu-
tathione and mitochondria. Front. Pharmacol. 2014, 5, 1–18.
[18] Krejsa, C. M., Franklin, C. C., White, C. C., Ledbetter, J. A.
et al., Rapid activation of glutamate cysteine ligase follow-
ing oxidative stress. J. Biol. Chem. 2010, 285, 16116–16124.
[19] Chen, Y., Shertzer, H. G., Schneider, S. N., Nebert, D. W.
et al., Glutamate cysteine ligase catalysis: dependence on
ATP and modifier subunit for regulation of tissue glu-
tathione levels. J. Biol. Chem. 2005, 280, 33766–33774.
[20] Huang, C. S., Chang, L. S., Anderson, M. E., Meister, A.,
Catalytic and regulatory properties of the heavy subunit
of rat kidney gamma-glutamylcysteine synthetase. J. Biol.
Chem. 1993, 268, 19675–19680.
[21] Njalsson, R., Norgren, S., Physiological and pathologi-
cal aspects of GSH metabolism. Acta Paediatr. 2005, 94,
132–137.
[22] Luo, J. L., Hammarqvist, F., Andersson, K., Wernerman, J.,
Surgical trauma decreases glutathione synthetic capacity
in human skeletal muscle tissue. Am. J. Physiol. 1998, 275,
E359–E365.
[23] Huang, C. S., He, W., Meister, A., Anderson, M. E., Amino
acid sequence of rat kidney glutathione synthetase. Proc.
Natl. Acad. Sci. USA 1995, 92, 1232–1236.
[24] Shi, Z. Z., Habib, G. M., Rhead, W. J., Gahl, W. A. et al.,
Mutations in the glutathione synthetase gene cause 5-
oxoprolinuria. Nat. Genet. 1996, 14, 361–365.
[25] Nefedova, Y., Fishman, M., Sherman, S., Wang, X. et al.,
Mechanism of all-trans retinoic acid effect on tumor-
associated myeloid-derived suppressor cells. Cancer Res.
2007, 67, 11021–11028.
C2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mnf-journal.com
10 J. Yin et al. Mol. Nutr. Food Res. 2015, 0,1–13
[26] Olson, K. R., Donald, J. A., Nervous control of circulation–
the role of gasotransmitters, NO, CO, and H2S. Acta His-
tochem. 2009, 111, 244–256.
[27] di Masi, A., Ascenzi, P., H2S: a “double face” molecule in
health and disease. Biofactors 2013, 39, 186–196.
[28] Peter, E. A., Shen, X. G., Shah, S. H., Pardue, S. et al., Plasma
free H2S levels are elevated in patients with cardiovascular
disease. J. Am. Heart Assoc. 2013, 2, e000387.
[29] Zhang, M., Shan, H., Chang, P., Wang, T. et al., Hydrogen
sulfide offers neuroprotection on traumatic brain injury in
parallel with reduced apoptosis and autophagy in mice.
PLoS One. 2014, 9, e87241.
[30] McBean, G. J., The transsulfuration pathway: a source of
cysteine for glutathione in astrocytes. Amino Acids 2012,
42, 199–205.
[31] Shibuya, N., Koike, S., Tanaka, M., Ishigami-Yuasa, M. et al.,
A novel pathway for the production of hydrogen sulfide
from D-cysteine in mammalian cells. Nat. Commun. 2013,
4, 1366.
[32] Stipanuk, M. H., Beck, P. W., Characterization of the enzymic
capacity for cysteine desulphhydration in liver and kidney
of the rat. Biochem. J. 1982, 206, 267–277.
[33] Shibuya, N., Kimura, H., Production of hydrogen sulfide
from D-cysteine and its therapeutic potential. Front. En-
docrinol. 2013, 4(87), 1–5.
[34] Stipanuk, M. H., Ueki, I., Dealing with methion-
ine/homocysteine sulfur: cysteine metabolism to taurine
and inorganic sulfur. J. Inher. Metab. Dis. 2011, 34,
17–32.
[35] Prudova, A., Bauman, Z., Braun, A., Vitvitsky, V. et al., S-
adenosylmethionine stabilizes cystathionine beta-synthase
and modulates redox capacity. Proc. Natl. Acad. Sci. USA
2006, 103, 6489–6494.
[36] Lu, M., Hu, L. F., Hu, G., Bian, J. S., Hydrogen sulfide pro-
tects astrocytes against H(2)O(2)-induced neural injury via
enhancing glutamate uptake. Free Radic. Biol. Med. 2008,
45, 1705–1713.
[37] Shibuya, N., Tanaka, M., Yoshida, M., Ogasawara, Y. et al.,
3-Mercaptopyruvate sulfurtransferase produces hydrogen
sulfide and bound sulfane sulfur in the brain. Antioxid. Re-
dox Signal. 2009, 11, 703–714.
[38] Chiku, T., Padovani, D., Zhu, W., Singh, S. et al., H2Sbio-
genesis by human cystathionine gamma-lyase leads to the
novel sulfur metabolites lanthionine and homolanthionine
and is responsive to the grade of hyperhomocysteinemia.
J. Biol. Chem. 2009, 284, 11601–11612.
[39] Stipanuk, M. H., De la Rosa, J., Hirschberger, L. L.,
Catabolism of cyst(e)ine by rat renal cortical tubules. J.
Nutr. 1990, 120, 450–458.
[40] Mikami, Y., Shibuya, N., Ogasawara, Y., Kimura, H., Hy-
drogen sulfide is produced by cystathionine gamma-
lyase at the steady-state low intracellular Ca2+con-
centrations. Biochem. Biophs. Res. Commun. 2013, 431,
131–135.
[41] Yang, G., Wu, L., Jiang, B., Yang, W. et al., H2Sasa
physiologic vasorelaxant: hypertension in mice with dele-
tion of cystathionine gamma-lyase. Science 2008, 322,
587–590.
[42] King, A. L., Bushan, S., Kondo, K., Nicholson, C. et al., Ge-
netic deficiency of the H2S producing enzyme, cystathion-
ine gamma-iyase (CSE) results in exacerbated myocardial
ischemia/reperfusion (MI/R) injury: role of eNOS dysfunc-
tion and decreased nitrite levels. Nitric Oxide 2013, 31, S31–
S31.
[43] Paul, B. D., Sbodio, J. I., Xu, R., Vandiver, M. S. et al., Cys-
tathionine ␥-lyase deficiency mediates neurodegeneration
in Huntington’s disease. Nature 2014, 509, 96–100.
[44] Bir, S. C., Kolluru, G. K., Shen, X. G., Wang, R. et al., CSE/H2S
rescues impaired arteriogenesis in mouse hind limb is-
chemia via IL-16 dependant monocyte recruitment and ex-
pression of bFGF. Nitric Oxide-Biol Ch 2013, 31, S36–S36.
[45]Huang,C.Y.,Yao,W.F.,Wu,W.G.,Lu,Y.L.etal.,En-
dogenous CSE/H2S system mediates TNF-induced insulin
resistance in 3T3-L1 adipocytes. Cell Biochem. Funct. 2013,
31, 468–475.
[46] Sha, L., Linden, D. R., Farrugia, G., Szurszewski, J. H., En-
dogenous H2S produced in prevertebral sympathetic gan-
glia predominantly by CSE in neurons and glia cells mod-
ulates central cholinergic synaptic input. Gastroenterology
2012, 142, S105–S105.
[47] Cooper, A. J., Biochemistry of sulfur-containing amino
acids. Ann. Rev. Biochem. 1983, 52, 187–222.
[48] Kabil, O., Banerjee, R., Redox biochemistry of hydrogen
sulfide. J. Biol. Chem. 2010, 285, 21903–21907.
[49] Mikami, Y., Shibuya, N., Kimura, Y., Nagahara, N. et al.,
Thioredoxin and dihydrolipoic acid are required for 3-
mercaptopyruvate sulfurtransferase to produce hydrogen
sulfide. Biochem. J. 2011, 439, 479–485.
[50] Yadav, P. K., Yamada, K., Chiku, T., Koutmos, M. et al., Struc-
ture and kinetic analysis of H2S production by human mer-
captopyruvate sulfurtransferase. J. Biol. Chem. 2013, 288,
20002–20013.
[51] Modis, K., Asimakopoulou, A., Coletta, C., Papapetropou-
los, A. et al., Oxidative stress suppresses the cellular
bioenergetic effect of the 3-mercaptopyruvate sulfurtrans-
ferase/hydrogen sulfide pathway. Biochem. Biophys. Res.
Commun. 2013, 433, 401–407.
[52] Li, M. Q., Nie, L. H., Hu, Y. J., Yan, X. et al., Chronic intermit-
tent hypoxia promotes expression of 3-mercaptopyruvate
sulfurtransferase in adult rat medulla oblongata. Auton.
Neurosci. 2013, 179, 84–89.
[53] Zhao, H., Chan, S. J., Ng, Y. K., Wong, P. T., Brain 3-
mercaptopyruvate sulfurtransferase (3MST): cellular local-
ization and downregulation after acute stroke. PLoS One
2013, 8, e67322.
[54] Liardon, R., Ledermann, S., Racemization kinetics of free
and protein-bound amino-acids under moderate alkaline
treatment. J. Agric. Food Chem. 1986, 34, 557–565.
[55] Martelli, A., Testai, L., Citi, V., Marino, A. et al., Arylth-
ioamides as H2S donors: L-cysteine-activated releasing
properties and vascular effects in vitro and in vivo. ACS
Med. Chem. Lett. 2013, 4, 904–908.
C2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mnf-journal.com
Mol. Nutr. Food Res. 2015, 0,1–13 11
[56] Roman, H. B., Hirschberger, L. L., Krijt, J., Valli, A. et al.,
The cysteine dioxgenase knockout mouse: altered cysteine
metabolism in nonhepatic tissues leads to excess H2S/HS
(-) production and evidence of pancreatic and lung toxicity.
Antioxid. Redox Signal. 2013, 19, 1321–1336.
[57] Mitchell, J., Paul, P., Chen, H. J., Morris, A. et al., Familial
amyotrophic lateral sclerosis is associated with a mutation
in D-amino acid oxidase. Proc. Natl. Acad. Sci. USA 2010,
107, 7556–7561.
[58] Stipanuk, M. H., Sulfur amino acid metabolism: pathways
for production and removal of homocysteine and cysteine.
Ann. Rev. Nutr. 2004, 24, 539–577.
[59] Stipanuk, M. H., Ueki, I., Dominy, J. E., Jr., Simmons, C. R.
et al., Cysteine dioxygenase: a robust system for regulation
of cellular cysteine levels. Amino Acids 2009, 37, 55–63.
[60] Bagley, P. J., Stipanuk, M. H., The activities of rat hepatic
cysteine dioxygenase and cysteinesulfinate decarboxylase
are regulated in a reciprocal manner in response to dietary
casein level. J. Nutr. 1994, 124, 2410–2421.
[61] Stipanuk, M. H., Dominy, J. E., Jr., Lee, J. I., Coloso, R. M.,
Mammalian cysteine metabolism: new insights into regu-
lation of cysteine metabolism. J. Nutr. 2006, 136, 1652S–
1659S.
[62] Dominy, J. E., Jr., Hirschberger, L. L., Coloso, R. M., Sti-
panuk, M. H., In vivo regulation of cysteine dioxygenase
via the ubiquitin-26S proteasome system. Adv. Exp. Med.
Biol. 2006, 583, 37–47.
[63] Dominy, J. E., Jr., Hirschberger, L. L., Coloso, R. M., Sti-
panuk, M. H., Regulation of cysteine dioxygenase degra-
dation is mediated by intracellular cysteine levels and
the ubiquitin-26 S proteasome system in the living rat.
Biochem. J. 2006, 394, 267–273.
[64] Jurkowska, H., Roman, H. B., Hirschberger, L. L., Sasakura,
K. et al., Primary hepatocytes from mice lacking cysteine
dioxygenase show increased cysteine concentrations and
higher rates of metabolism of cysteine to hydrogen sulfide
and thiosulfate. Amino Acids 2014, 46, 1353–1365.
[65] Perry, T. L., Norman, M. G., Yong, V. W., Whiting, S.
et al., Hallervorden-Spatz disease: cysteine accumulation
and cysteine dioxygenase deficiency in the globus pallidus.
Ann. Neurol. 1985, 18, 482–489.
[66] Jiang, Y., Widger, L. R., Kasper, G. D., Siegler, M. A.
et al., Iron(II)-thiolate S-oxygenation by O2: synthetic mod-
els of cysteine dioxygenase. J. Am. Chem. Soc. 2010, 132,
12214–12215.
[67] Che, X., Gao, J., Liu, Y., Liu, C., Metal vs. chalcogen compe-
tition in the catalytic mechanism of cysteine dioxygenase.
J. Inorg. Biochem. 2013, 122,1–7.
[68] Ueki, I., Stipanuk, M. H., 3T3-L1 adipocytes and rat adi-
pose tissue have a high capacity for taurine synthesis by
the cysteine dioxygenase/cysteinesulfinate decarboxylase
and cysteamine dioxygenase pathways. J. Nutr. 2009, 139,
207–214.
[69] de la Rosa, J., Stipanuk, M. H., Evidence for a rate-limiting
role of cysteinesulfinate decarboxylase activity in taurine
biosynthesis in vivo. Comp. Biochem. Physiol. B Comp.
Biochem. 1985, 81, 565–571.
[70] Kumar, P., Maurya, P. K., L-Cysteine efflux in erythrocytes
as a function of human age: correlation with reduced glu-
tathione and total anti-oxidant potential. Rejuvenation Res.
2013, 16, 179–184.
[71] Jones, D. P., Park, Y., Gletsu-Miller, N., Liang, Y. et al.,
Dietary sulfur amino acid effects on fasting plasma cys-
teine/cystine redox potential in humans. Nutrition 2011, 27,
199–205.
[72] Yin, J., Ren, W., Liu, G., Duan, J. et al., Birth oxidative stress
and the development of an antioxidant system in newborn
piglets. Free Radic. Res. 2013, 47, 1027–1035.
[73] Yin, J., Wu, M. M., Xiao, H., Ren, W. K. et al., Development
of an antioxidant system after early weaning in piglets. J.
Anim. Sci. 2014, 92, 612–619.
[74] Yin, J., Duan, J., Cui, Z., Ren, W. et al., Hydrogen peroxide-
induced oxidative stress activates NF-[small kappa]B and
Nrf2/Keap1 signals and triggers autophagy in piglets. RSC
Adv. 2015, 5, 15479–15486.
[75] Yin, J., Ren, W. K., Wu, X.S., Yang, G. et al., Oxidative stress-
mediated signaling pathways: a review. J. Food Agric. En-
viron. 2013, 11, 132–139.
[76] Sen, U., Sathnur, P. B., Kundu, S., Givvimani, S. et al., In-
creased endogenous H2S generation by CBS, CSE, and
3MST gene therapy improves ex vivo renovascular relax-
ation in hyperhomocysteinemia. Am.J.Physiol.CellPhys-
iol. 2012, 303, C41–C51.
[77] Sun, X. L., Zeng, X. N., Zhou, F., Dai, C. P. et al., KATP channel
openers facilitate glutamate uptake by GluTs in rat primary
cultured astrocytes. Neuropsychopharmacology 2008, 33,
1336–1342.
[78] Trotti, D., Danbolt, N. C., Volterra, A., Glutamate trans-
porters are oxidant-vulnerable: a molecular link between
oxidative and excitotoxic neurodegeneration? Trends Phar-
macol. Sci. 1998, 19, 328–334.
[79] Cho, Y., Bannai, S., Uptake of glutamate and cysteine in
C-6 glioma cells and in cultured astrocytes. J. Neurochem.
1990, 55, 2091–2097.
[80] Ripps, H., Shen, W., Review: taurine: a “very essential”
amino acid. Mol. Vis. 2012, 18, 2673–2686.
[81] De la Puerta, C., Arrieta, F. J., Balsa, J. A., Botella-Carretero,
J. I. et al., Taurine and glucose metabolism: a review. Nutr.
Hosp. 2010, 25, 910–919.
[82] Das, J., Roy, A., Sil, P. C., Mechanism of the protective action
of taurine in toxin and drug induced organ pathophysiology
and diabetic complications: a review. Food Funct. 2012, 3,
1251–1264.
[83] Borges-Santos, M. D., Moreto, F., Pereira, P. C., Ming-Yu,
Y. et al., Plasma glutathione of HIV(+) patients responded
positively and differently to dietary supplementation with
cysteine or glutamine. Nutrition 2012, 28, 753–756.
[84] Badaloo, A., Hsu, J. W., Taylor-Bryan, C., Green, C. et al.,
Dietary cysteine is used more efficiently by children with
severe acute malnutrition with edema compared with those
without edema. Am. J. Clin. Nutr. 2012, 95, 84–90.
[85] Bauchart-Thevret, C., Stoll, B., Chacko, S., Burrin, D. G., Sul-
fur amino acid deficiency upregulates intestinal methionine
C2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mnf-journal.com
12 J. Yin et al. Mol. Nutr. Food Res. 2015, 0,1–13
cycle activity and suppresses epithelial growth in neona-
tal pigs. Am. J. Physiol. Endocrinol. Metabol. 2009, 296,
E1239–E1250.
[86] Bauchart-Thevret, C., Cottrell, J., Stoll, B., Burrin, D. G.,
First-pass splanchnic metabolism of dietary cysteine in
weanling pigs. J. Anim. Sci. 2011, 89, 4093–4099.
[87] Elshorbagy, A. K., Nurk, E., Gjesdal, C. G., Tell, G. S.
et al., Homocysteine, cysteine, and body composition in the
Hordaland Homocysteine Study: does cysteine link amino
acid and lipid metabolism? Am. J. Clin. Nutr. 2008, 88,
738–746.
[88] Zoratti, R., A review on ethnic differences in plasma triglyc-
erides and high-density-lipoprotein cholesterol: is the lipid
pattern the key factor for the low coronary heart disease
rate in people of African origin? Eur. J. Epidemiol. 1998, 14,
9–21.
[89] Lee, S., Han, K. H., Nakamura, Y.,Kawakami, S. et al., Dietary
L-cysteine improves the antioxidative potential and lipid
metabolism in rats fed a normal diet. Biosci. Biotechnol.
Biochem. 2013, 77, 1430–1434.
[90] Senthilkumar, G. P., Thomas, S., Sivaraman, K., Sankar,
P. et al., Study the effect of S-methyl L-cysteine on lipid
metabolism in an experimental model of diet induced obe-
sity. J. Clin. Diagn. Res. 2013, 7, 2449–2451.
[91] Sit, M., Yilmaz, E. E., Tosun, M., Aktas, G., Effects of N-
acetyl cysteine on lipid levels and on leukocyte and platelet
count in rats after splenectomy. Niger. J. Clin. Pract. 2014,
17, 343–345.
[92] Bettzieche, A., Brandsch, C., Hirche, F., Eder, K. et al., L-
Cysteine down-regulates SREBP-1c-regulated lipogenic en-
zymes expression via glutathione in HepG2 cells. Ann. Nutr.
Metab. 2008, 52, 196–203.
[93] Tsuboyama-Kasaoka, N., Shozawa, C., Sano, K., Kamei,
Y. et al., Taurine (2-aminoethanesulfonic acid) deficiency
creates a vicious circle promoting obesity. Endocrinology
2006, 147, 3276–3284.
[94] Chen, W., Guo, J. X., Chang, P., The effect of taurine on
cholesterol metabolism. Mol. Nutr. Food Res. 2012, 56,
681–690.
[95] McGavigan, A. K., O’Hara, H. C., Amin, A., Kinsey-Jones, J.
et al., L-Cysteine suppresses ghrelin and reduces appetite
in rodents and humans. Int. J. Obes. 2014, 39, 447–455.
[96] Jordi, J., Herzog, B., Camargo, S. M., Boyle, C. N. et al., Spe-
cific amino acids inhibit food intake via the area postrema
or vagal afferents. J. Physiol. 2013, 591, 5611–5621.
[97] Kawai, M., Sekine-Hayakawa, Y., Okiyama, A., Ninomiya, Y.,
Gustatory sensation of (L)- and (D)-amino acids in humans.
Amino Acids 2012, 43, 2349–2358.
[98] Nelson, G., Chandrashekar, J., Hoon, M. A., Feng, L.
et al., An amino-acid taste receptor. Nature 2002, 416,
199–202.
[99] Ingenbleek, Y., The nutritional relationship linking sul-
fur to nitrogen in living organisms. J. Nutr. 2006, 136,
1641S–1651S.
[100] Zhang, X., Li, H., Liu, G., Wan, H. et al., Differences in plasma
metabolomics between sows fed dL-methionine and its hy-
droxy analogue reveal a strong association of milk com-
position and neonatal growth with maternal methionine
nutrition. Br. J. Nutr. 2015, 113, 585–595.
[101] Li, H., Wan, H., Mercier, Y., Zhang, X. et al., Changes in
plasma amino acid profiles, growth performance and in-
testinal antioxidant capacity of piglets following increased
consumption of methionine as its hydroxy analogue. Br. J.
Nutr. 2014, 112, 855–867.
[102] Di Buono, M., Wykes, L. J., Ball, R. O., Pencharz, P. B., Dietary
cysteine reduces the methionine requirement in men. Am.
J. Clin. Nutr. 2001, 74, 761–766.
[103] Elshorbagy, A. K., Valdivia-Garcia, M., Mattocks, D. A. L.,
Plummer, J. D. et al., Effect of taurine and N-acetylcysteine
on methionine restriction-mediated adiposity resistance.
Metabolism 2013, 62, 509–517.
[104] Elshorbagy, A. K., Valdivia-Garcia, M., Mattocks, D. A. L.,
Plummer, J. D. et al., Cysteine supplementation reverses
methionine restriction effects on rat adiposity: significance
of stearoyl-coenzyme A desaturase. J. Lipid Res. 2011, 52,
104–112.
[105] Green, C. O., Badaloo, A. V., Hsu, J. W., Taylor-Bryan, C.
et al., Effects of randomized supplementation of methion-
ine or alanine on cysteine and glutathione production dur-
ing the early phase of treatment of children with edematous
malnutrition. Am. J. Clin. Nutr. 2014, 99, 1052–1058.
[106] Huang, L., Hogewind-Schoonenboom, J. E., van Dongen,
M. J. A., de Groof, F. et al., Methionine requirement of the
enterally fed term infant in the first month of life in the
presence of cysteine. Am. J. Clin. Nutr. 2012, 95, 1048–1054.
[107] Sawamoto, O., Kyo, S., Kaneda, S., Harada, M. et al., Four-
week intravenous repeated dose toxicity study of L-cysteine
in male rats. J. Toxicol. Sci. 2003, 28, 95–107.
[108] Ren, W., Yin, J., Wu, M., Liu, G. et al., Serum amino acids
profile and the beneficial effects of L-arginine or L-glutamine
supplementation in dextran sulfate sodium colitis. PloS
One 2014, 9, e88335.
[109] Nguyen, D., Hsu, J. W., Jahoor, F., Sekhar, R. V., Effect of
increasing glutathione with cysteine and glycine supple-
mentation on mitochondrial fuel oxidation, insulin sensi-
tivity, and body composition in older HIV-infected patients.
J. Clin. Endocrinol. Metabol. 2014, 99, 169–177.
[110] Sekhar, R. V., Patel, S. G., Guthikonda, A. P., Reid, M.
et al., Deficient synthesis of glutathione underlies oxida-
tive stress in aging and can be corrected by dietary cysteine
and glycine supplementation. Am. J. Clin. Nutr. 2011, 94,
847–853.
[111] Thakurta, I. G., Chattopadhyay, M., Ghosh, A., Chakrabarti,
S., Dietary supplementation with N-acetyl cysteine, alpha-
tocopherol and alpha-lipoic acid reduces the extent of ox-
idative stress and proinflammatory state in aged rat brain.
Biogerontology 2012, 13, 479–488.
[112] Jain, S. K., L-Cysteine supplementation as an adjuvant ther-
apy for type-2 diabetes. Can J Physiol Pharmacol. 2012, 90,
1061–1064.
[113] Sekhar, R. V., McKay, S. V., Patel, S. G., Guthikonda,
A. P. et al., Glutathione synthesis is diminished in pa-
tients with uncontrolled diabetes and restored by dietary
C2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mnf-journal.com
Mol. Nutr. Food Res. 2015, 0,1–13 13
supplementation with cysteine and glycine. Diabetes Care
2011, 34, 162–167.
[114] Jain, S. K., Velusamy, T., Croad, J. L., Rains, J. L. et al., L-
cysteine supplementation lowers blood glucose, glycated
hemoglobin, CRP, MCP-1, and oxidative stress and inhibits
NF-kappaB activation in the livers of Zucker diabetic rats.
Free Radic. Biol. Med. 2009, 46, 1633–1638.
[115] Blouet, C., Mariotti, F., Azzout-Marniche, D., Mathe, V. et al.,
Dietary cysteine alleviates sucrose-induced oxidative stress
and insulin resistance. Free Radic. Biol. Med. 2007, 42,
1089–1097.
[116] Yi, D., Hou, Y., Wang, L., Ding, B. et al., Dietary N-
acetylcysteine supplementation alleviates liver injury in
lipopolysaccharide-challenged piglets. Br. J. Nutr. 2014,
111, 46–54.
[117] Kim, C. J., Kovacs-Nolan, J., Yang, C., Archbold, T. et al.,
L-cysteine supplementation attenuates local inflammation
and restores gut homeostasis in a porcine model of colitis.
Biochim. Biophys. Acta 2009, 1790, 1161–1169.
[118] Chitapanarux, T., Tienboon, P., Pojchamarnwiputh, S., Lee-
larungrayub, D., Open-labeled pilot study of cysteine-rich
whey protein isolate supplementation for nonalcoholic
steatohepatitis patients. J. Gastroenterol. Hepatol. 2009, 24,
1045–1050.
[119] Alhamdan, A. A., The effect of dietary supplementation of
N-acetyl-L-cysteine on glutathione concentration and lipid
peroxidation in cigarette smoke-exposed rats fed a low-
protein diet. Saudi Med. J. 2005, 26, 208–214.
[120] Parachikova, A., Green, K. N., Hendrix, C., LaFerla, F. M.,
Formulation of a medical food cocktail for Alzheimer’s dis-
ease: beneficial effects on cognition and neuropathology in
a mouse model of the disease. PLoS One 2010, 5, e14015.
[121] Okawa, H., Morita, T., Sugiyama, K., Cysteine supplementa-
tion decreases plasma homocysteine concentration in rats
fed on a low-casein diet in rats. Biosci. Biotechnol. Biochem.
2007, 71, 91–97.
[122] Ma, K. U., Liu, Y., Zhu, Q., Liu, C. H. et al., H2S donor, S-
propargyL-cysteine, increases CSE in SGC-7901 and cancer-
induced mice: evidence for a novel anti-cancer effect of
endogenous H2S? Plos One 2011, 6, e20525.
[123] Vidal, K., Breuille, D., Serrant, P., Denis, P. et al., Long-term
cysteine fortification impacts cysteine/glutathione home-
ostasis and food intake in ageing rats. Eur. J. Nutr. 2014,
53, 963–971.
[124] Elshorbagy, A. K., Valdivia-Garcia, M., Mattocks, D. A.,
Plummer, J. D. et al., Cysteine supplementation reverses
methionine restriction effects on rat adiposity: significance
of stearoyl-coenzyme A desaturase. J. Lipid Res. 2011, 52,
104–112.
[125] Wu, G., Functional amino acids in nutrition and health.
Amino Acids 2013, 45, 407–411.
[126] Wu, G., Amino Acids: Biochemistry and Nutrition, CRC
Press, Boca Raton, F L 2013.
[127] Fang, Y. Z., Yang, S., Wu, G., Free radicals, antioxidants, and
nutrition. Nutrition 2002, 18, 872–879.
[128] Wu, G., Fang, Y. Z., Yang, S., Lupton J. R. et al., Glutathione
metabolism and its implications for health. J. Nutr. 2004,
134, 489–492.
[129] Li, X. L., Bazer, F. W., Gao, H., Jobgen, W. et al., Amino acids
and gaseous signaling. Amino Acids 2009, 37, 65–78.
[130] Hou, Y. Q., Wang, L., Yi, D., Wu, G., N-acetylcysteine and in-
testinal health: a focus on mechanisms of its actions. Front.
Biosci. 2015, 20, 872–891.
[131] Yi, D., Hou, Y. Q., Wang, L., Ding, B. Y. et al., Dietary N-
acetylcysteine supplementation alleviates liver injury in
lipopoly-saccharide-challenged piglets. Br. J. Nutr. 2014,
111, 46–54.
[132] Hou, Y.Q., Wang, L., Yi, D., Ding, B. Y. et al., N-Acetylcysteine
reduces inflammation in the small intestine by regulat-
ing redox, EGF and TLR4 signaling. Amino Acids 2013, 45,
513–522.
C2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.mnf-journal.com
