REVI EW

ARTI CLE
Citrulline: pharmacological perspectives and
its role as an emerging biomarker in future
Shilpa N. Kaore
a
*, Hanmant S. Amane
a
, Navinchandra M. Kaore
b
a
Department of Pharmacology, Peoples College of Medical Sciences, Bhanpur Road, Bhopal, Madhya Pradesh,
462037, India
b
Department of Microbiology, Peoples College of Medical Sciences, Bhanpur Road, Bhopal, Madhya Pradesh, 462037,
India
Keywords
biomarker,
citrulline,
nitric oxide,
rheumatoid,
T cell,
vasodilatation
Received 17 February 2012;
revised 18 May 2012;
accepted 8 June 2012
*Correspondence and reprints:
shinaka@rediffmail.com
ABSTRACT
L-citrulline is a naturally occurring non-essential amino acid, an intermediate in
urea cycle and conditionally essential in intestinal pathology. It is a potent hydro-
xyl radical scavenger and much more effective precursor of arginine and nitric
oxide (NO) than arginine itself so exploited in therapeutics. Plasma citrulline con-
centration is used by clinicians to assess functional enterocyte mass in various
chronic and acute small bowel pathologies like short bowel syndrome that has
become an indication in clinical practice. Its supplementation is likely to be used
in conditions like erectile dysfunction, sickle cell anemia, short bowel syndrome (to
restore nitrogen balance), hyperlipidemia, cancer chemotherapy, hypercholestre-
mia, in hyperoxic lung damage, urea cycle disorders, Alzheimers disease, multi-
infarct dementia and as an immunomodulator. Its emerging role as a biomarker in
intestinal pathology and early diagnosis of Rheumatoid arthritis has spread consid-
erable interest. Antibody detection to Anti-cyclic citrullinated peptide (ACCP) anti-
bodies can be recommended for early detection of RA decreasing joint damage and
deformity, because these are detected well before the onset of disease manifesta-
tions of RA. The test is highly specic than RF (Rheumatoid factor), with moderate
sensitivity, but much useful in differentiating RA from other disorders. Further
studies and exploration is required in these areas.
I NTRODUCTI ON
L-citrulline is a naturally occurring non-essential amino
acid, present in mammals and also in each living
organism. It is produced by the body naturally and
also found in some foods like watermelons, cucum-
bers, pumpkins, muskmelons, bitter melons, squashes,
gourds. Its basic function is detoxication of ammonia
via conversion to urea. Citrullines name is actually
derived from the Latin word for watermelonCitrullus
vulgarisbecause it was rst isolated from it in 1930
[1,2], unusually rich in citrulline (CIT) [3]. It may
also function as a potent hydroxyl radical scavenger
[4].
Citrulline, made from ornithine and carbamoyl phos-
phate, is a component of the urea cycle in the liver [5].
CIT is synthesized from arginine (ARG) and glutamine
in enterocytes. CIT entering into kidney, vascular endo-
thelium, and other tissues can be readily converted to
ARG and nitric oxide (NO) [6], and this ARG is made
available for utilization by peripheral tissues. Citrulline
is formed mainly in eneterocytes from glutamine, liver
contributing to minimal [7]. About 80% of CIT is con-
verted in the kidney to ARG [7,8], nally converting
ARG to CIT and NO and serving as a potent ARG pre-
cursor [911]. This is carried out via argininosuccinate
synthase (ASS) to l-argininosuccinate and subsequently
to ARG by argininosuccinate lyase (ASL) [12]. Evi-
dence suggest argininosuccinate pathway in pig [13
15], converts CIT to ARG in cerebral vascular endothe-
lium, which is a constant, neuronal source of NO for
inducing cerebral vasodilatation [16]. CIT has very spe-
cic metabolism, it is not metabolized in liver/intestine
[6]. Hence, CIT is essential to make ARG, in turn, ARG
2012 The Authors Fundamental and Clinical Pharmacology 2012 Socie te Franc aise de Pharmacologie et de The rapeutique
Fundamental & Clinical Pharmacology 27 (2013) 3550 35
doi: 10.1111/j.1472-8206.2012.01059.x
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is needed to produce NO, that acts as an endogenous
vasodilator [17].
Nitric oxide is synthesized from ARG by tetrahydrobi-
opterin (BH4)-dependent NO synthase [18], dictating a
vital role of ARG in maintaining health and treating a
wide array of chronic diseases. NO improves endothe-
lial function by elevating cyclic guanosine monophos-
phate (cGMP) [19]. Decreased NO production and
endothelial dysfunction associated with ageing is corre-
lated with decreased NOS activity in elderly and with
progressive endothelial dysfunction [20].
There is growing evidence for the role of NO, regu-
lating insulin sensitivity, oxidation of energy substrates,
a key role in immune response [21], neurological func-
tion and hemodynamics in animals and humans [22].
NO released from endothelium is an important regula-
tor of vascular tone [23] inhibitor of platelet and leuco-
cyte aggregation and adhesion [23,24], as well as
inhibitor of cell proliferation [25,26], so plays a crucial
role in regulation of vascular disease undoubtedly.
However, as ARG supplementation was not as effective
and reliable as that of CIT, CIT may be a promising
and more successful therapy. Thus, supplementation
with CIT is a novel therapeutic approach in conditions
of ARG and NO deciency [27].
Moreover, the other side of the coin is that lower lev-
els of NO protect cells from apoptosis, while excessive
NO is toxic [28] and may lead to apoptosis [29]. This
is because NO causes endoplasmic reticulum (ER) stress
that induces a transcription factor, CAAT/enhancer
binding protein (C/EBP), homologous protein (CHOP),
and leads to apoptosis [29]. So, ER calcium stores can
be the future targets of NO, and ER stress pathway is
an important mechanism of NO-mediated apoptosis in
various cells, including macrophages, microglia, and
pancreatic beta cells [29].
Previous clinical studies show ARG to improve ow-
mediated vasodilation (FMD) and thus endothelial func-
tion because of normalization of ARG/ADMA ratio
[20], where asymmetric dimethylarginine inhibition
(ADMA) is as an endogenous inhibitor of NO synthase
[30]. But it is now realized that both lack as well as
excess of NO production can have very important
implications in health and disease [27]. Hence, inhibi-
tion of excessive NO production is also a promising
future therapeutic target. Another essential AA, Gluta-
mine (GLn) inhibits nitric oxidergic neurovascular
transmission by undetermined mechanisms [31].
Citrulline is released by small intestine continuously,
taken up by kidney and metabolized into ARG, while
no uptake by liver protects from hepatic degradation of
CIT. Another means of sustaining protein homeostasis
is ARGCITARG cycle in kidney. Thus, plasma CIT
may be a good marker of intestinal failure in short
bowel syndrome (SBS) where a decreased level of CIT is
directly proportional to severity of intestinal disease or
functional intestinal mass [32]. So, CIT may be a con-
ditionally essential amino acid (AA) in stress [33], or
when intestinal function is compromised [32]. This
notion is proved in SBS in rats where CIT is able to
restore nitrogen balance, increase ARG levels and
increase muscle protein content as well as muscle pro-
tein synthesis (+90%) in elderly malnourished rats
[32]. Moreover, it also has a potential as a supplement
for total parenteral nutrition (TPN) in SBS patients
because it additionally prevents muscle atrophy too,
not seen with ARG supplementation [34].
Discovery of CIT as ARG and NO precursor, and the
close link between ARG and CIT, has urged consider-
able interest and is being explored further. Thus, CIT
supplementation can be an alternative to ARG supple-
mentation for clinical use [35], and even watermelon
can be used as a substitute for supplementing CIT to
increase plasma levels of ARG [2]. Hence, recently CIT
has raised tremendous interest in scientic community,
which was previously considered to be only a compo-
nent/intermediate of urea cycle [9].
The aim of this review is to summarize current
knowledge and future aspects in therapeutics and to
dene its role as a biomarker. The values of plasma cit-
rulline can aid in diagnosis and severity of intestinal
failure and, possibly, for monitoring the bowel func-
tion. Its role in early diagnosis of rheumatoid arthritis
is emerging as a promising biomarker that needs fur-
ther exploration.
PHARMACOKI NETI CS OF ORAL
CI TRULLI NE
Citrulline supplementation shows signicant increase
in plasma ARG and augmentation of NO-dependent
signalling mechanisms in a dose-dependent manner.
Oral CIT, increased AUC and C (max) of plasma ARG
concentration dose-dependently more effectively than
ARG supplementation (P < 0.01). The highest dose of
citrulline (3 g bid) increased the C (min) of plasma
ARG and improved ARG/ADMA ratio signicantly from
baseline (P < 0.01, 95% condence interval (CI) 66,
121). Moreover, urinary nitrate and cGMP were
increased signicantly creatinine (P = 0.01, 95% CI 8,
2012 The Authors Fundamental and Clinical Pharmacology 2012 Socie te Franc aise de Pharmacologie et de The rapeutique
Fundamental & Clinical Pharmacology 27 (2013) 3550
36 S.N. Kaore & H.S. Amane
58) and from 38 3.3 to 50 6.7 nmol/mmol(1)
creatinine (P = 0.04, 95% CI 0.4, 24), respectively.
However, it failed to demonstrate improvement in ow-
mediated vasodilatation (FMD) over baseline, which is
in contradiction to pooled analysis of all FMD data that
documents a correlation between increased ARG/
ADMA ratio and improvement in FMD [36].
Citrulline is formed mostly in enterocytes; maximum
citrulline (80%) is converted in the kidney to ARG [7].
Chronic renal insufciency results in decreased uptake
of CIT and release of ARG that are reduced by 60
70%, and the study depicts linear relationship between
CIT extraction and ARG release in subjects with nor-
mal renal function [37]. Decreases in citrulline levels
are clinically relevant as they reect a decrease in
functional mass of enterocytes [7,38]. CIT ingestion
decreases QT interval in healthy subjects which means
it shortens the time required for completion of myocar-
dial depolarization and repolarization [39], thus CIT
may be associated with cardiovascular risks [40].
ADVERSE DRUG REACTI ONS
Short-term administration of CIT is safe and well toler-
ated. No adverse effects were observed in healthy sub-
jects that given different loading doses (2, 5, 10, or
15 g CIT) [9]. Further, CIT levels increased in plasma
but not in ARG with the highest dose of CIT that may
be due to saturation of renal conversion of CIT to ARG
[9]. Watermelon-induced citrullinemia may occur as
a result of consumption of large quantities of water-
melon, which comprises of elevated plasma citrulline
and, to a lesser extent, ARG, in the absence of orotic
or arginosuccinicaciduria or hyperammonemia. So,
physicians and laboratory persons should be aware of
this phenomenon and is also important in manage-
ment of urea cycle and related disorders [41]. There is
dearth of reliable scientic data regarding its use in
pregnancy and lactation.
DRUG I NTERACTI ONS
Currently no authentic scientic documentation
regarding the drug interactions was found.
PHARMACODYNAMI CS
Studies with arginine
Arginine supplementation is found to reduce glucose
in chemically induced diabetic rats [4244], ZDF rats
(Zucker diabetic fatty rat) [45], reduce excess fat in
ZDF rats and patients with diabetes [46]and show
improvement in vascular reactivity in diabetes [47]
and hypercholesterolemic subjects [48]. No benecial
effect was seen in terms of increase NO availability
and improving athletic performance in humans [49].
However, studies on ARG supplementation docu-
ments for improvement in NO production and is thus
helpful in CV diseases associated with endothelial
dysfunction such as hypertension, heart failure, athero-
sclerosis [50], diabetic vascular disease, and ischemia-
reperfusion injury, but the effects are not seen on
chronic ARG supplementation, so CIT supplementation
holds promise in this regard [6]. ARG in long term
improves hepatic and peripheral sensitivity to insulin
in type 2 diabetes (T2DM) patients [51].
To conclude, ARG supplementation has failed to pro-
vide consistent results in clinical trials reasons being
ARG metabolism in liver, ARG toxicity and role of
cofactor tetrahydrobiopterin in NO production and its
relation with ARG availability [27], all contributing to
arginine paradox [52]. In addition, oral ARG supple-
mentation is rendered ineffective because of extensive
presystemic and systemic elimination due to gut bacte-
ria and hepatic and gut arginase activity [19,36,53],
while CIT is subjected to systemic metabolism only and
not to presystemic one [19]. Additionally, ARG
enhance arginase expression and activity both, thus
reducing effectiveness of ARG, in contrast, and CIT not
only inhibits arginase activity but also does not induce
tissue arginase [6].
Arginine and glutamine studies
As discussed, GLn interferes with CIT-mediated NO pro-
duction [54], similarly found to modulate (increase)
the effects of ARG too. GLn supplementation is found
to reduce morbidity and mortality in critically ill
patients fed parenterally in selected patients [33]. GLn
regulates gut barrier function, antioxidant status and
immune-inammatory response [33], improve nitrogen
balance so could be added to total parenteral nutrition
[55]. There is now an international consensus to
recommend GLN supplementation (0.20.4 g/kg/day of
L-glutamine) in critically ill patients receiving paren-
teral nutrition [56].
Arginine and GLn are non-essential AA, but both
become conditionally essential AA in stress with their
metabolism closely related [33,55]. GLn is an essential
AA and a possible precursor of ARG and thus for NO
synthesis in murine macrophages, and its consumption
2012 The Authors Fundamental and Clinical Pharmacology 2012 Socie te Franc aise de Pharmacologie et de The rapeutique
Fundamental & Clinical Pharmacology 27 (2013) 3550
Citrulline and its future perspectives 37
in sepsis probably represents NO production [57,58].
The simultaneous administration of ARG and GLn
resulted in additive or synergistic effects on gut barrier
function and inammatory response, but the effects in
critically ill are not documented [33]. Thus, both needs
to be further explored and documented for benecial/
detrimental effects. ARG and GLn consumption also
increases in response to high cholesterol diet, thus they
may have pharmacological implications in hypercholes-
terolemia [59].
Citrulline more efcacious than arginine
Citrulline is an effective substitute to restore NO pro-
duction in situations of limited ARG availability [54].
Studies in healthy volunteers support that oral CIT
supplementation raises blood ARG levels more effec-
tively than ARG supplementation itself [60]. Acute oral
CIT administration more efciently raises the plasma
ARG levels vs. long-term ARG supplementation [6],
increasing plasma ARG levels to about 227% with
3.8 g CIT(within 4 h) compared to only 90% rise with
equivalent dose of ARG [6,61]. These facts make CIT, a
better substitute for ARG and NO supplementation,
than ARG itself [6,8].
Citrulline and studies on watermelon
Watermelon is found to accumulate CIT, ARG, and
glutamate in its leaves under drought condition [4].
Chronic consumption of watermelon increases plasma
ARG and NO concentration of in healthy subjects
[2,62], and thus watermelon pomace juice reduces
cardiovascular (CV) risk factors, improves glycemic con-
trol, ameliorates vascular dysfunction in obese animals
with type 2 diabetes mellitus (T2DM) [62] and in
genetic obese model of NIDDM (Zucker diabetic fatty,
i.e., ZDF rat) [62]. Results demonstrate increased plasma
ARG levels by CIT intake from watermelon [2,41].
Additionally, high sensitivity of ZDF rats to circulat-
ing ARG establishes a useful model to identify nutri-
tional treatments for metabolic syndrome in obesity
and diabetes [62]. The increased serum levels of both
ARG and NO in ZDF rats suggest ARG synthesis from
CIT and the subsequent conversion of ARG to NO [62].
STUDI ES ON CI TRULLI NE
Citrulline in sickle cell anemia
Citrulline (oral) may be given in sickle cell disease as
ARG precursor required as a substrate in the argi-
nine-nitric oxide pathway for endogenous nitrovasodi-
lation and vasoprotection. The ARG-induced
vasoprotection is partly mediated by NO-induced inhi-
bition of endothelial damage and inhibition of adhe-
sion and activation of leukocytes, so is valuable in
palliative therapy of sickle cell disease (SCD) for which
it has cleared Phase II trials, decreasing complications
and increasing overall well-being of these patients
[10]. Further studies are indicated in this area
(Boxes 1 and 2; Figure 1).
Box 1
Citrulline natural sources
Sources Watermelon (Citrullis vulgaris), cucumbers,
pumpkins, muskmelons, bitter melons, squashes,
gourds.
Chronic consumption:
o improves glycemic control in NIDDM.
o improves vascular dysfunction.
Consumption of large quantities of Watermelon results
in Watermelon-induced citrullinemia.
Plants accumulate citrulline in leaves in drought condi-
tions that works as antioxidant and helps to combat
stress, as in Kalahari desert.
Box 2
Citrulline supplementation major effects
A non-essential amino acid, donor of arginine & NO,
and conditionally essential amino acid in intestinal
pathology.
Major pharmacological actions:
o Antioxidant
o Vasodilatation
o Decrease leucocyte migration
o Restore nitrogen balance & increase muscle protein
content as well as muscle protein synthesis
o Improves endothelial dysfunction
o Increased arginosuccinate synthase (ASS) expres-
sion in cancer cells
o Preserve anti-inammatory mediator response (in
sepsis)
Citrulline and cardiovascular effects
Impaired endothelial NO production is because of the
reduction in nitric oxide synthase (NOS), therefore,
increasing ARG availability either by ARG therapy or
by arginase inhibition may provide benets in future in
hypertension [27].
Nitric oxide synthase exists in three isoforms: neuro-
nal NOS (nNOS, NOS 1), inducible NOS (iNOS, NOS 2),
2012 The Authors Fundamental and Clinical Pharmacology 2012 Socie te Franc aise de Pharmacologie et de The rapeutique
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38 S.N. Kaore & H.S. Amane
and endothelial (eNOS, NOS 3) that convert ARG
to NO and CIT [63]. In addition, ADMA has very low
circulating levels in humans and is found to be an
endogenous inhibitor of all three isoforms of NOS [30].
The ARG/ADMA ratio is one of the determinants of NO
production [64], and NO activates soluble guanylyl
cyclase (sGC) in smooth muscles leading to increase
in intracellular cGMP causing vasodilation [65]; this
Figure 1 Schematic representation of synthesis of citrulline.
2012 The Authors Fundamental and Clinical Pharmacology 2012 Socie te Franc aise de Pharmacologie et de The rapeutique
Fundamental & Clinical Pharmacology 27 (2013) 3550
Citrulline and its future perspectives 39
process being essential for endothelial function and dis-
turbed NO production in the human endothelium attri-
butes to endothelial dysfunction [63,63,66]. Under
ischemic conditions, NO is synthesized from nitrite, in
acidic conditions, via non-enzymatic pathway [67]
mainly in tissues [68].
Studies to analyze the cardiovascular effects with
CIT and ARG supplementation show improvement in
right ventricular function (RVF) by increasing RVF
ejection fraction [69], and probably decreasing sys-
tolic pulmonary artery pressure because of benecial
effects on endothelial function [70] in heart failure
patients with preserved ejection fraction. CIT is a
safer way of delivering ARG for endothelial and
immune cells as well as can prevent excessive uncon-
trolled NO production [71] that exerts deleterious
effects of its own.
CIT sustainedrelease in cardiovascular diseases
Further evaluation of newer formulation of CIT,
sustained release (SR) CIT, suggests SR to have more
sustained levels of CIT and ARG compared to immedi-
ate release CIT throughout the experimental study,
thus favouring SR use of SR formulation for benecial
effects in cardiovascular diseases and atherosclerosis
[72]. This may further help in extending its benecial
action to other clinical conditions too.
Citrulline in hypertension
Observations state that hypertensive patients had lower
arginine-to-citrulline ratio than normotensive patients
[26]. A known fact is that hypertension is often associ-
ated with NO deciency, oxidative stress, increased
reactive oxygen species, and a disturbed constrictor-
dilator balance in the kidney [73]. Recently, melatonin
is found to exert antihypertensive effect in young spon-
taneously hypertensive rats (SHRs) owing to restora-
tion of the NO pathway by reduction in plasma ADMA,
preservation of renal ARG availability, attenuation of
oxidative stress [74]. This may be due to the defects in
the renal citrullinearginine pathway or ARG reabsorp-
tion potentially reduce renal NO in prehypertensive
SHR [75]. It was also observed that if NO availability is
increased perinatally, it reduces blood pressure, so CIT
supplementation in SHR resulted in increased renal NO
signicantly [75]. In addition, CIT supplementation
overcomes the early renal NO deciency and its sequels
in male and female SHRs [75]. A recent study in rats
further evaluated the effect of maternal caloric restric-
tion in offspring and found less number of nephrons
and renal dysfunction and also developed hypertension
that were reversed with maternal CIT supplementation
with long-term antihypertensive effects [76]. Future
studies are required to support this notion.
Citrulline in hyperlipidemia
A recent analysis evaluated the role of CIT, and ARG
in hypercholesterolemic rats shows the reversal of
increased serum levels of aspartate aminotransferase
(AST), alanine aminotransferase (ALT), urea with con-
comitant increase in high density cholesterol (HDL-c)
and NO. The data indicate CIT as well as ARG good
efcacy as hypocholesterolemic and hypolipidemic
agents in rats [77].
Citrulline in diabetes
In addition to reduction in glucose levels, CIT may ben-
et the underlying endothelial dysfunction [7881] in
diabetes. In metabolic syndrome, one of the hallmarks
is decreased endothelial synthesis and bioavailability of
NO [47]. Previous studies demonstrate the activation of
the argininecitrulline cycle in macrophages in an
autoimmune condition, increasing ARG synthesis from
CIT, sustaining increase in NO production, and proba-
bly related to autoimmune destruction of pancreatic
beta-cells in insulin-dependent diabetes mellitus (IDDM)
[82]. In IDDM, the destruction of beta-cells, which are
very much vulnerable to NO-induced apoptosis, is
found to be due to excessive NO production leading to
apoptosis [29], while lower levels of NO do not appar-
ently cause severe damage in mouse beta-cells [83].
A study on healthy volunteers revealed that CIT
may reduce NO-mediated pancreatic secretion or
increased insulin clearance, and does not elevate
plasma insulin in response to exercise in patients who
also received CIT supplementation [84]. But a recent
study contradicts to this, where citrulline maleate (CM)
supplementation signicantly increased the insulin lev-
els in response to exercise returning to basal levels at
recovery [85].
Watermelon juice is shown to have benecial effects
by increase in ARG availability and improve glycemic
control and vascular dysfunction in T2DM [62].
Citrulline in erectile dysfunction
In single blind, short-term study in men with erectile
dysfunction (ED) (erection hardness score of 3) L-citrul-
line was given 1.5 g/day for a month, which con-
cluded it to be a safe and psychologically well accepted
and reported as very satisfying by patients, although
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40 S.N. Kaore & H.S. Amane
less effective than phosphodiesterase type-5 enzyme
inhibitors, with improvement in erection hardness
score from 3 to 4 [86]. So, it may prove effective in
mild-to-moderate ED that requires further research in
this area.
Citrulline as immunomodulator
Citrulline production is signicantly reduced in sepsis
because of diminished de novo conversion of ARG
and NO, reducing CIT and ARG availability in septic
patients and transgenic mice [8,27], in part due to
ADMA release [87]. Higher ADMA levels are corre-
lated with higher mortality rate in sepsis [87,88]. In
sepsis, there is a complex interplay between pro- and
anti-inammatory cytokines and endothelial NO may
be a key factor in regulating this response. Further
observations found increased proteolysis in sepsis but
decreased ARG levels suggesting inadequate secondary
synthesis as a result of decreased levels of CIT too
[87].
L-citrulline (CIT) supplementation seems to be a valu-
able means of supplementing ARG, favourably
increases NO availability, and correlates with alteration
of the systemic response of mediators and cytokines
with varied degrees of sepsis. CIT preserved the anti-
inammatory mediator response, decreased proinam-
matory mediator response (IL-6 and resistin) without
impairing the secretion of anti-inammatory mediators
(IL-10 and adiponectin), thus acting as an immuno-
modulator [52]. So, to conclude, CIT may be a safe
means of immunomodulation that preserves the anti-
inammatory mediator response.
Citrulline: in arginase associated T-cell
dysfunction
Interestingly, T lymphocytes are found to depend on
ARG for their proliferation, zeta-chain peptide forma-
tion, T-cell receptor complex expression and develop-
ment of memory [89,90]. This makes obvious that
T-cell abnormalities like decreased proliferation and loss
of zeta chain are observed in cancer, after trauma [89]
and may provide new insights into T-cell dysfunction
[90].
Citrulline is found to have the potential as a substi-
tute for arginase-associated T-cell dysfunction. The
basis for this is the molecular capability of T cells to
increase CIT membrane transport and up-regulating
ASS expression and thus converting CIT to ARG in
invitro studies, thus escaping the ill effects of ARG
depletion [91]. Hence, CIT supplementation can pre-
serve T-cell proliferation and prevent the loss of CD3
zeta chain under conditions of low ARG [91]. So, new
drug targets as well as new insights may be explored
in future.
Citrulline: role in treatment for cancer
Decreased ASS expression is correlated with decreased
sensitivity of tumour cells, CIT is found to increase this
sensitivity because of concomitant increase in AS
expression. So, combination therapy of CIT supplemen-
tation with human recombinant arginase, that is,
HuArgI (Co)-PEG5000 (HuArgI) is selectively cytotoxic
to a fraction of human cancer cell lines in tissue cul-
ture, including some melanomas, mesotheliomas, acute
myeloid leukemias, hepatocellular carcinomas, pan-
creas adenocarcinomas, prostate adenocarcinomas,
lung adenocarcinomas, osteosarcomas, and small-cell
lung carcinomas. Unfortunately subsets of normal
human tissues are also found to be sensitive to HuArgI
with CIT supplementation, including umbilical endo-
thelial cells, bronchial epithelium, neurons, and renal
epithelial cells. Further, these invitro ndings suggest
the combination therapy to be a therapeutic agent for
some ASS-decient tumors [92].
Citrulline: role in dementia of Alzheimers disease
and in multi-infarct dementia
The cerebrospinal uid (CSF) levels of various amino
acids were examined in dementia, with the conclusion
that the CSF/serum levels of CIT were signicantly
higher in comparison with control group in multi-
infarct dementia [93]. This is supported further by
elevated NOS activity found in microvessels of brain in
Alzheimers disease (AD), raising vascular NO produc-
tion, exerting neurotoxicity, and is responsible for sus-
ceptibility to neuronal injury and cell death in AD
[94]. Some studies contradict this notion and suggest
decreased NO production [95,96], to play a role in
neurodegenerative disorders.
Asymmetric dimethylarginine inhibition, which is
hydrolyzed by dimethylarginine dimethylaminohydro-
lase enzyme into CIT and dimethylamine, is also found
elevated specically in neurons displaying cytoskeletal
abnormalities and oxidative stress in AD, but not in
early stages of AD [97]. So, as found in experimental
studies, pharmacological intervention using NO donors
and/or NO suppressors could delay or at least minimize
brain lesion development and further progression of
brain pathology and dementia [98,99]. Signicantly
elevated CIT levels were found in multiple system atro-
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Citrulline and its future perspectives 41
phy [95]. Further research may prove or disprove the
use of CIT modulators in brain lesions in humans.
Citrulline: can it improve aerobic function/energy
production?
Observations suggest high-intensity exercises increasing
ammonia levels in skeletal muscles [], ammonia in turn
activates phosphofructokinase and prevents oxidation
of pyruvate to acetyl CoA, thus leading to exhaustion
and exercise-induced fatigue [100,101]. Further, the
urea cycle being responsible for detoxication of ammo-
nia [102], while skeletal muscle buffers ammonia via
transamination reactions [103]. Experimental studies
prove that ARG, CIT, and ornithine supplementation
suppressed the accumulation of ammonia after exercise
and prolongs the time taken for exhaustion [103]. So,
there is possibility of improvement in treadmill time
with CIT, but in contrast, in humans, prior CIT inges-
tion was actually found to reduce it and became
exhausted [84].
A recent study in cyclists, also analysed the effect of
prior administration of CM on exercise, concluded that
there was a signicant rise in plasma levels of CIT,
ARG, ornithine, urea, creatinine, and nitrite and signif-
icantly decreased the isoleucine concentration from
basal measures to after exercise, that is, essential
amino acids (AA) show signicant decrease while non-
essential AA show signicant rise after exercise. To
add, citrulline maleate (CM) can increase the produc-
tion of branched chain AA in response to exercise [85].
CM ingestion signicantly reduced fatigue sensation,
because of increase in (by 34%) the rate of oxidative
ATP production during exercise and increase (20%) in
the rate of phosphocreatine recovery after exercise in a
clinical trial, suggesting larger contribution of oxidative
ATP synthesis to energy production [104]. This
improves aerobic energy production in muscles and
exercise tolerance, signicantly enhancing aerobic per-
formance and prolongation of onset of muscular fati-
gue. CM also limits muscle fatigue or skeletal muscle
dysfunction induced by bacterial endotoxins [105,106].
Recent studies documented on effect on CIT supple-
mentation in healthy animals found to have ergogenic
effect associated with improvement in muscular con-
traction efciency in healthy rats [107], and improve-
ment in athletic performance in mice may be probably
due to facilitation of detoxication of ammonia via the
urea cycle and inhibition of additional glycolysis [102].
A recent human trial supports the notion, where CM
single dose (8 g) increased athletic performance in
high-intensity anaerobic exercises with short rest times
and relieved postexercise muscle soreness that supports
athletes undergoing intensive preparation may gain
prots of CIT ingestion [108]. Thus, CIT may be used
as an agent to increase exercise capacity for various
reasons.
Citrulline for urea cycle disorders
Citrulline may be used for the detection of inborn
errors of metabolism of urea cycle, responsible for
removal of ammonia, that are fortunately quite rare.
The rst step in the urea cycle is the reaction of ammo-
nia and bicarbonate using adenosine triphosphate
(ATP) and catalyzed by the enzyme carbamoyl phos-
phate synthetase (CPS) to produce carbamoyl phos-
phate. The second step is the reaction of carbamoyl
phosphate and L-ornithine to produce L-citrulline, cata-
lyzed by the enzyme ornithine transcarbamylase (OTC).
It is interesting to note that deciencies of either of
these two enzymes lead to low serum levels of L-citrul-
line and are treated with oral L-citrulline. In the long-
term management, diet treatment is also a part of
management and treatment must be individualized
[109].
Citrulline: an antioxidant?
Citrulline in plants protects from stress situations, like
conditions of drought. A unique phenomenon
observed in watermelon is massive accumulations
amount of CIT in its leaves, making its photosynthetic
apparatus functional even in prolonged drought and
strong sunlight. Hence, CIT concentration in water-
melon, in Kalahari Desert, is higher. Under stressful
conditions, reactive oxygen species, including hydroxyl
radicals, increases oxidative damage to plants affecting
their nucleic acids, proteins, carbohydrates, and lipids
[3].
Studies suggest potent radical scavenging action of
CIT [4], affording protection from oxidative injuries
[4,110,111] and maintenance of water status [111].
This notion is supported by a study in healthy cyclists,
where prior CIT supplementation (6 g) reduced oxida-
tive damage by priming of polymorphonuclear neu-
trophils for oxidative burst without evidence of
oxidative damage and progressive decrease in reactive
oxygen species (ROS) production and markers of oxida-
tive damage [112]. Therefore, it is postulated that CIT,
probably a potent hydroxyl scavenger, tends to protect
DNA and metabolic enzymes against oxidative stress,
which needs further exploration.
2012 The Authors Fundamental and Clinical Pharmacology 2012 Socie te Franc aise de Pharmacologie et de The rapeutique
Fundamental & Clinical Pharmacology 27 (2013) 3550
42 S.N. Kaore & H.S. Amane
Citrulline in intestinal pathology
Citrulline is easily taken up by gut by help of transport-
ers and is then taken up by enterocytes, and it has
been conrmed by pharmacokinetic studies (in rats)
that citrulline supplementation is found to be more ef-
cient than with ARG supplementation to provide ARG
[113]. CIT is found to increase protein synthesis during
refeeding in rodents with short bowel syndrome, aging,
malnutrition, and improves nitrogen balance in fed
healthy humans [114]. CIT pre-treatment improves
integrity of gut barrier, and preservation of ileum
mucosa was observed in mice thus reducing bacterial
translocation [115], similar effects are seen with ARG
too [116]. So CIT, rather than ARG is the limiting
amino acid in situations of intestinal failure which is
proved in rat model of SBS, since CIT supplementation
improved protein synthesis and ARG availability [71].
These studies suggest that CIT have a strong poten-
tial for total parenteral nutrition after massive intesti-
nal resection (SBS) [34] that cause increase in ARG
pool and restores nitrogen balance [117], whereas
long-term supplementation of ARG intraduodenally in
rats failed to show benecial results in intestinal ische-
mia and reperfusion injury [118].
CI TRULLI NE AS A BI OMARKER
Citrulline as a biomarker in intestinal disease
Serum citrulline is emerging as an innovative biomar-
ker candidate for the assessment of intestinal function
[119]. As CIT is not involved in protein synthesis or
nutrition product, it is now an established biomarker of
enterocyte functional metabolic mass in adults and
children [120,121]. It can assess the remnant length
of small bowel in intestinal diseases like short bowel,
extensive enteropathies, intestinal toxicity of chemo-
therapy and radiotherapy [120]. Normal plasma citrul-
line levels range between 30 and 50 lM independent of
nutritional status [120]. The levels <10 lM may indi-
cate objective threshold for parenteral nutrition in case
of intestinal failure that allows monitoring of intestinal
function except in cases of signicant renal failure
[120]. This revealed that decreased plasma citrulline
concentration reects a decrease in functional mass of
enterocytes [7] provided that renal function is normal
[32].
It has been further assessed as a non-invasive mar-
ker of intestinal failure and monitoring of bowel func-
tion [7,38], and serial plasma citrulline assay helps to
monitor residual small bowel adaptation in children
[38]. Studies show serum citrulline was signicantly
lower in short bowel syndrome (SBS) patients and thus
could be accurately taken as simple, non-invasive bio-
marker for assessing the severity of intestinal failure
and may prove as a candidate marker for the gut-tro-
phic effects of bowel rehabilitation therapies [122].
Two separate human studies supports postabsorptive
plasma CIT concentration as a marker of functional
absorptive bowel length that also allows distinction of
transient to permanent intestinal failure in SBS patients
[123] and as a marker of reduced enterocyte mass in
patient with villous atrophy diseases [124]. In this
postabsorptive state, CIT availability would be
increased and would be able to maintain basal insulin
secretion and minimal protein synthesis [32].
It can be taken as a prognostic marker for parenteral
nutrition weaning when bowel mass is affected and as
a deciding factor between parenteral and enteral nutri-
tion therapy [121,124]. Questions have been raised on
acceptability of serum CIT as a biomarker in acute
intestinal failure in critically ill patients that needs fur-
ther evaluation [125].
Anti-cyclic citrullinatedpeptide antibodies, a novel
biomarker of rheumatoid arthritis
Citrulline may be also considered as a non-protein AA,
in the context that CIT cannot be incorporated into
proteins during translation process (CIT do not have its
own trinucleotide codon), but it is found in some pro-
teins because of post-translational modication of these
proteins and the proteins thus modied are called cit-
rullinated proteins. Of interest, there are evidences now
to suggest the posttranslational modications to be
responsible for the initial triggering of autoimmunity
and the breaking of tolerance [126]. A human study
suggests citrullination to be an inammation-depen-
dent process as it is present in many inammatory tis-
sues [127].
Citrulline is also a posttranslationally modied ARG
residue [128], and surprisingly, an essential part of B-
cell epitope found in antibodies (Ab) in rheumatoid
arthritis (RA), that is, citrullination of an un-identied,
but RA-specic autoantigen [129]. Citrullination in RA
(ARGCIT conversion, deaminated arginine) is carried
out by peptidylarginine deiminase (PADI) [130], an
enzyme that appears to be hormonally controlled
[129]. Genetic variations in PADI, PADI4, increase sus-
ceptibility to RA because of increased enzymatic activ-
ity [130], further the posttranslational protein
modication unfold the protein with the loss of positive
2012 The Authors Fundamental and Clinical Pharmacology 2012 Socie te Franc aise de Pharmacologie et de The rapeutique
Fundamental & Clinical Pharmacology 27 (2013) 3550
Citrulline and its future perspectives 43
charge in ARG residues that alters the antigenicity of
self-proteins leading to autoimmunity and chronic
inammation [131].
It is now revealed that autoantibodies in RA contain-
ing the unusual AA CIT are specically found in serum
of RA patients [128]. Ab against citrullinated proteins/
peptides (laggrin) [132], that is, detection of Anti-
cyclic citrullinatedpeptide (ACCP) antibodies are highly
specic [131,133137] biomarker in RA [130], other
biomarkers for RA being rheumatic factor (RF) and anti-
perinuclear factor (APF) and anti-keratin antibodies
(AKA) [128,136]. Moreover, the frequency of false-posi-
tive results is lower with ACCP antibody detection [134]
than with RF [138], thus this modern biomarker of best
diagnostic value [139] needs further evaluation [140],
for early detection and preventing joint damage and
deformity. Further, it has similar diagnostic value in
patients with established or long duration disease, and is
a reliable marker of severe erosive disease and in RF
seronegative cases [139]. Another related biomarker,
equally sensitive as ACCP antibodies [136,141], that
needs to be analyzed further is antibodies to modied
citrullinized vimentin (AMCV), which is signicantly
correlated with early detection of RA [140], and sub-
clinical atherosclerosis in RA [141].
As these CIT-containing antibodies (Ab) are detected
early, are specic, and detected well before the appear-
ance of other manifestations of the disease [128], that
may also indicate its role in the autoimmune response
[133] and pathogenesis [130,131]. Citrullinated anti-
gens (Ag) are expressed in inamed joint and can be
detected early before the disease manifests [131].
ACCP-ELISA assays suggest diagnostic sensitivities
between 69.6% and 77.5% and specicities between
87.8% and 96.4% [142]. To conclude, estimation of
ACCP antibodies is highly specic [143] but not abso-
lutely specic in RA [135], can be exploited as a bio-
marker for RA, and be detected early in the course of
disease [128]. This may improve the prognostic value
in RA patients [140] and show new insights into etiol-
ogy, and pathogenesis of disease may be revealed
[128,129].
However, it also raises a future query whether ACCP
antibodies have better prognostic signicance than RF
[144], will it really replace RF [145]? A recent study
has raised doubts because it failed to improve the per-
formance of American College of Rheumatology (ACR)
1987 criteria in diagnosing early RA in combination
with the detection of ACCP antibody [146]. Future
studies may have an answer to this, or the strategy
may be to use RF in combination with ACCP antibod-
ies for denitive diagnosis of RA [147], but the concur-
rent detection of ACCPAb and RF will surely increase
the chances of differentiating RA from other diseases
[132,148]. Further data collection may answer the
question and that whether the ACCP titers might prove
as predictors of efcacy of anti-TNF therapy [148].
Other effects of citrulline
Effect on proteins and hormones
In healthy subjects, effects on plasma amino acids and
hormonal patterns show that CIT, ornithine (ORN) and
ARG plasma concentrations were affected according to
CIT dose, while plasma insulin and growth hormone
were unaffected [9]. A recent double-blind study in
healthy volunteers did not show any correlation of CIT
supplementation with changes in protein metabolism
[114].
As discussed previously, citrulline increases protein
synthesis, during refeeding in rodents with SBS, aging
and malnutrition, and improves nitrogen balance in
fed healthy humans; its effect on proteins and hor-
mones was evaluated [114]. Data indicated that CIT
supplementation is able to restore nitrogen balance,
generate large amounts of ARG in rats with SBS and
increase muscle protein content (+20%) as well as
muscle protein synthesis (+90%) in elderly malnour-
ished rats [32, 113]. So, it may be concluded that CIT
increases ARG and ornithine concentrations [114] and
plays a crucial role in maintaining protein hemostasis,
improving muscle mass related to malnutrition [113]
and further understanding of molecular mechanisms
may help in developing new strategies in malnourished
patients with compromised intestinal functions [32].
Effects of amino acids on hair strength
Human studies report considerable amount of ARG
deposition on or in hair bres from coloring agents
[150], while decreased amounts of ARG and CIT were
found in damaged hairs in users of Relaxers and
decreased CIT has been associated with inammation
[151]. Study reports indicate that when coloring
agents were partially replaced with ARG, it decreased
the oxidative change in tensile strength of hair by pre-
venting the undesirable attack by hydrogen peroxide
on hair proteins and hair surface lipids [150]. So, pro-
spective studies need to be undertaken to know
whether or how relaxers induce inammation [151]
and whether ARG or CIT can substantially reduce hair
damage and fragility.
2012 The Authors Fundamental and Clinical Pharmacology 2012 Socie te Franc aise de Pharmacologie et de The rapeutique
Fundamental & Clinical Pharmacology 27 (2013) 3550
44 S.N. Kaore & H.S. Amane
CONCLUSI ON
L-citrulline, a naturally occurring non-essential amino
acid, found in plants and animals has scope beyond
amino acid. Apart from its role in protein homeostasis,
and as an intermediate in urea cycle, L-citrulline is
useful in detecting inborn errors of urea cycle, also
found to be a potent hydroxyl radical scavenger and
much more effective precursor of ARG and NO than
ARG itself. CIT supplementation is likely to be highly
exploited in therapeutic conditions like erectile dysfunc-
tion, sickle cell anemia, SBS, hyperlipidemia, cancer
chemotherapy, sustained release preparation in cardio-
vascular diseases, and to increase protein content in
malnourished as well as elderly patients. Recently, its
role as a biomarker has been realized in intestinal
pathology, which may also be used for monitoring
patients with SBS receiving parenteral nutrition.
Recently, anti-cyclic citrullinated peptide (ACCP) anti-
bodies, ACCP-ELISA, can be recommended for early
detection of rheumatoid arthritis (RA) decreasing joint
damage and deformity as these are detected well before
the onset of manifestations of RA with high specicity
and moderate sensitivity much useful in differentiating
RA from other disorders. But future studies are
required for further analysis of biomarker as a sole
diagnostic entity. Human studies have supported that
CIT supplementation reduces oxidative stress after
cycling, so may be utilized as an antioxidant in
future. CIT alters the systemic response of mediators
and cytokines in sepsis and acts as an immunomod-
ulator. Moreover, multiple system atrophy is associ-
ated with elevated CIT levels, so role of CIT
modulators can be explored in certain brain lesions.
Further studies are needed to explore the pleotropic
effects of CIT supplementation in different therapeutic
conditions.
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