Professional Documents
Culture Documents
Beneficial Effects of The Amino Acid Glycine: Mini Reviews in Medicinal Chemistry June 2016
Beneficial Effects of The Amino Acid Glycine: Mini Reviews in Medicinal Chemistry June 2016
net/publication/303951608
CITATIONS READS
19 2,966
3 authors:
Verónica Guarner
Instituto Nacional de Cardiología
137 PUBLICATIONS 1,403 CITATIONS
SEE PROFILE
Some of the authors of this publication are also working on these related projects:
All content following this page was uploaded by Israel Pérez-Torres on 03 August 2018.
REVIEW ARTICLE
Keywords: Anti-inflammatory, antioxidant effects, cardiovascular effects, glycine ligands, glycine, metabolic effects.
of the condition. Plasma glycine concentrations fall in isolated perfused or stored organs have also reported
volunteers infected with sandfly fever, and a decreased improved conditions after glycine treatment as shown in
concentrations of glycine, serine and cysteine were observed Table 2. In vivo studies in experimental animals have also
in patients suffering from severe trauma [9]. tested glycine as a protector molecule and the results of such
studies are summarized in Table 3. Finally some studies on
Many in vitro studies involving culture of different cells the beneficial effects of glycine after its clinical application
types have demonstrated beneficial effects of the addition of
are shown in Table 4. The reported beneficial effects of
glycine. These studies are summarized in Table 1. Studies on
glycine are discussed in the present review.
Protects from cell injury against tert-butylhydroperoxide, decreases tubular release of lactate
1mM or 2mM
dehydrogenase [10-13]
Renal proximal tubules 0.8mM Diminishes injury from hypoxia and hypoxia-reoxygenation [14-16]
Protects from hypoxia and/or hypoxia-reoxygenation injury and injury due to pH restoration from
0.2 and 0.4mM 6.2 to 7.4 [21, 22]
Hepatocytes Prevents from cold ischemic injury and injury due to warm reoxygenation [23]
Protects from cellular injury that is independent of glutathione synthesis in hepatocytes exposed to
3mM
cold ischemia [24]
2-10mM Protects cells and non-specifically blocks influx of different ions (sodium, cobalt, nickel) [25, 26]
200µM Diminishes the activation of the Kupffer cells by action of lipopolysaccharide [27]
Kupffer cells
Blunts LPS-induced calcium influx and increases Cl- intake [28]
0.1-1mM
Lymphocytes Inhibits proliferation and blunts concanavalin A induced calcium fluxes [29]
Alveolar macrophages 10µM Blunts calcium influx, increases Cl- intake and decreases superoxide and TNFα secretion [5]
Neutrophils 0.3mM
Splenic macrophages 0.55mM Inhibibits the activation of neutrophils [30], splenic macrophages [31] and CD4 lymphocytes [32]
CD4 T lymphocytes
Rat cortical neuron cultures 1000-2000µM Decreases hypoxic injury in neurons (DIV4-20) [38]
Blocks injury induced by re-energization and pH normalization following induced ischemia and
HL-1 cardiac myocytes 3mM
increases cell viability [39]
Protects against tert-butylhydroperoxide injury only when previous incubation with glycine is done
Human intestinal epithelial cell 1 or 5mmol 1-1
for 24 hours [40]
Beneficial Effects of the Amino Acid Glycine Mini-Reviews in Medicinal Chemistry, 2016, Vol. 16, No. 0 3
Prevents liver injury due to perfusion first of a hypoxic and then an oxygenated buffered salt
3,6 and 12mM solution [41]
Isolated liver
Decreases liver injury induced by tert-butylhydroperoxide [42]
Langendorff-perfused heart Prevents from injury associated with pH normalization upon reperfusion following ischemia [39]
10mM Decreases injury of the transplanted liver and increases survival of the recipients [45]
Cold-stored liver Decreases hepatocellular injury but without having a protective effect on bile formation [46]
Ex vivo lung perfusion model 5mM Ameliorates lung injury upon warm reperfusion [49]
Decreases injury of the transplanted liver and increases survival of the recipient (iv. infusion to the
130mg·kg-1 donor) [53]
Liver
Attenuates inflammatory response for mechanical manipulation [54]
Decreases mortality, liver necrosis, lung damage and serum tumor necrosis factor after LPS
5% for 3 days
intravenous injection [55]
In metabolic syndrome animals it increases arachidonic acid concentration and GlyRβ expression, it
decreases systolic blood pressure, concentration of triglycerides and insulin in plasma, HOMA
index, albuminuria and creatinine clearance, percentage of COX pathway inhibition, concentration
1% for 8 weeks of PGE2 and TXB2 in kidney perfusate, the expression of PLA2 COX-1 and COX-2 in kidney
homogenate.
In histopathologic studies of the kidney it decreases endothelial edema, thickened glomerular basal
Kidney membrane irregulary and area of obliteration [56]
Decreases ischemia-reperfusion injury and improves renal function (higher GFR and lower plasma
5% for 2 weeks combined creatinine) [57]
with 100mg·kg-1 bolus Decreases renal vascular resistance, leading to an increase in renal plasma flow and hence in GFR.
It also decreases proximal tubular reabsorption under physiological conditions [58]
4g/kg Decreases ischemia injury and improves survival following reperfusion [60]
(Table 3) Contd….
Skeletal muscle 750mg·kg-1 Preserves muscle function, decrease edema and necrotic injury [67]
Lung 3.75 g Effectively improves graft function following transplantation (iv. infusion) [51]
Improves early post-ischemic right ventricular compliance and decreases myocardial injury (iv.
Heart 136mg·kg-1
infusion) [68]
Hemorrhagic shock 5% fed for 4 days Increases survival and decreases injury of lung, kidney and liver [69]
Neurologic therapy Ameliorates cognitive deficits, dementia and increases antipsychotic treatment of schizophrenia
0.8g·kg-1·day
[70-72]
Acute ischemic Sublingual treatment improved clinical (functional) outcome and tended to decrease the 30 day
0.5, 1or 2g·5 days
stroke mortality [74]
Glycine is oxidatively degraded to CO2, NH4+, NADH At high-doses, glycine may cause toxic effects. The
and a methylene group by the mitochondrial glycine absorption of 1.5% glycine was associated with a
cleavage system which is NAD+-dependent. The methylene progressive increase in bradycardia and death when an
group is then accepted by tetrahydrofolate, thus forming N5, intravenous infusion of irrigating fluid was given to mice or
N10-methylenetetrahydrofolate [21]. The reactions catalyzed rabbits [80]. Toxicity was also observed during transurethral
by the glycine cleavage system and by serine hydroxymethyl resection of the human prostate and endometrial resection
transferase are reversible and thus can also be used for the [80-81]. Further studies are needed to investigate the safe
synthesis of glycine. Furthermore glycine is also formed range of usage of this aminoacid that may improve disease
from glyoxylate aminotranferase [75]. conditions and to test the diverse routes for its
administration.
The pervasive herbicide, glyphosate, may be disrupting
glycine homeostasis. Glyphosate is the most-used herbicide
2. RECEPTORS OF GLYCINE
in the world. It suppresses the synthesis of pyrrole, needed
for chlorophyll, heme and corrin [76]. It does so by acting as To exert its actions, glycine binds to different receptors.
a glycine mimetic in the first step of the reaction that The glycine receptor anion channel (GlyR) is the most
produces pyrrole, interfering with aminolevulinic acid studied; however, there is evidence of GlyR-independent
dehydratase activity [77]. The World Health Organization mechanisms for glycine cytoprotection in different tissues
recently relabeled it as “probably carcinogenic”. The human [82]. Other possible receptors of glycine are N-methyl-D-
population is currently facing a health care crisis due to the aspartate receptor (NMDA) receptor and type 1 and 2
rising incidence of multiple chronic conditions such as glycine transporters (GlyT1 and GlyT2).
diabetes, obesity, and gut dysbiosis which might be caused
in part by the consumption of glyphosate [78]. Although 2.1. Glycine Receptor
evidence is accumulating that suggests that glyphosate might
be acting as a disruptive ligand in glycine receptors or as a Glycine binds to GlyR, which is a Cl- selective channel
disruptor of enzymes that metabolize glycine, further or pore embedded in the cellular membrane. This receptor is
research is needed to verify this aspect of glyphosate's a pentameric anion channel generally consisting of four α
toxicity [79]. Many of the functions of glycine make sense and one β subunits. Its α3, α4 and β the subunits interact with
in the context of glyphosate's known toxicology profile and gephyrin to anchor it to the membrane [35]. Activation of
therefore, the excessive use of this compound may be the this glycine-gated Cl- channel is a mechanism widely
reason why excessive supplementation of glycine is postulated to explain the beneficial effects of glycine [31].
warranted [76-79].
Beneficial Effects of the Amino Acid Glycine Mini-Reviews in Medicinal Chemistry, 2016, Vol. 16, No. 0 5
The pentameric GlyR is localized in the postsynaptic subunit can lead to a different regulation. Studies have
neuronal membrane of the spinal cord [83] but it is also demonstrated that long-term glycine exposure blunts
present in a wide variety of cells such as the renal proximal activation of alveolar macrophages and neutrophils but not
tubular cells, hepatocytes, endothelial cells, lung, stomach of Kupffer cells possibly suggesting the participation of the
and intestinal cells [84]. GlyR was originally purified from different types of the GlyR subunit in regulation of
the rat spinal chord by affinity chromatography on amino- desensitization. Long-term dietary glycine down regulates
strychnine-agarose columns [85] and its primary structure Cl- channel function not only in Kupffer cells but also in
was determined by complementary DNA cloning [31]. neuronal tissue which depends on phosphorylation of the α-
Furthermore, GlyR is also a member of the nicotinic subunit. The GlyR α3-subunit is present in Kupffer cells,
acetylcholine, 5-HT3, and γ-aminobutyric acid A (GABAA) peritoneal neutrophils and in splenic and alveolar
receptor family of ligand-gated ion channels which are macrophages [93]. Expression of the GlyR α4-subunit is
expressed in the central nervous system, macrophages, present in Kupffer cells, neutrophils, splenic and alveolar
leukocytes, renal cells, Kupffer cells, kidney, endothelial macrophages but not in the spinal cord of rats [28]. Alveolar
cells and sperms [86]. macrophages contain a GlyR α4-subunit [5]. Furthermore, the
β-subunit mRNA was detected in Kupffer cells, splenic
It is formed by four α-subunits (α1-4) with about 48 kDa
macrophages, neutrophils, and alveolar macrophages
and a β-subunit with about 58 kDa in weight. The α-subunit
neutrophils, splenic and alveolar macrophages but no in the
genes are highly homologous, having a primary structure spinal cord of rats [28].
that displays 80-90% amino acid sequence identity while the
β-subunit has a sequence similarity of 47% with the α1 - GlyR are targets for number of different modulators
subunit [87]. The α-subunits determine the ligand including ethanol, anaesthetics, picrotoxin and zinc (Zn2+).
recognition, binding and gating sites and the β subunit is The divalent Zn2+cation exerts a complex biphasic modulation
linked to cytoskeletal proteins [88]. The five subunits of of α1, α2 and α1β GlyR [94]. Modulation by Zn2+ potentiates
GlyR are arranged pseudo-symmetrically around a central GlyR activation at low concentrations (0-1-10 µM) and
ion-conducting pore. This topology includes a large NH2- attenuates sensitivity to glycine at higher concentrations
terminal extracellular domain that contains disulfide bridges (<10µM) [95]. Low concentrations of Zn2+ (0.01-10µM) in
of cysteine in the agonist binding site. Furthermore, the spinal cord potentiate glycinergic currents by increasing
hydropathy analysis originally predicted an arrangement of the apparent glycine affinity without changing the saturating
four α-helical transmembrane domains per subunit and current magnitude, whereas higher concentrations (>10µM)
inclusion of a β-sheet in the transmembrane domains [89]. inhibit the current by reducing the apparent glycine affinity.
The functional phosphorylation sites on the α1- and β- Zn2+ chelators decrease the amplitude, duration and
subunits of GlyR have been mapped to the intracellular frequency of GlyR [96].
cysteine loop and are able to modulate its function [90].
The alkaloid strychnine is a potent competitive inhibitor
GlyR activation depends on the presence of extracellular of the GlyR acting already at 1-10µM concentrations. Apart
Cl-. When the GlyR is activated, the resulting Cl- flux moves from strychnine, there are other antagonist which bind to the
the membrane potential rapidly toward the Cl- equilibrium GlyR with nanomolar affinities such as the steroid RU 5135
potential [91]. Depending on the value of the equilibrium and 1,5-diphenyl-3,7diazaadamantan-9-ol. Inhibition of
potential relative to the cell resting potential, the Cl- flux GlyR causes convulsions, while enhancement of the glycine
may cause either a depolarization or an hyperpolarization of receptor causes central nervous system depression and
the cell membrane, as well as inhibition of voltage- muscle relaxation [97]. Evidence in spinal cord from GlyR
dependent opening of calcium (Ca2+) channels [92]. The protein modification experiments indicated that the
opening of the glycine-sensitive anion channels causes a strychnine and glycine binding sites are mutually interactive
rapid allosteric transition via a series of concerted molecular but not identical [98]. Strychnine and its analogs are highly
motions that delay the breakage of the membrane linkages as selective and extremely potent competitive antagonists of
well as the formation of the large pores or channels in glycine with a dissociation constant of 5-10 nM [99]. In
adenosine triphosphate (ATP) depletion [35]. Indeed, vertebrates, strychnine poisoning abolishes glycinegic
substitution of Cl- with an impermeable anion such as inhibition by blocking GlyR function. The consequence is
gluconate prevents the inhibitory effect of glycine on over-excitation of the motor system resulting in muscular
agonist-induced increases in Ca2+. In addition, influx of Cl- convulsions [100]. Resveratrol can also inhibit GlyR without
could also inactivate the inositol triphosphate (IP3)-gated causing convulsions [97]. Ginkgolide B, a platelet activating
Ca2+ channel and blunt release of Ca2+ from intracellular factor antagonist is also a specific and potent blocker of
stores [30]. The IP3-gated chloride channel on the GlyR-gated currents in dissociated rat hippocampal
endoplasmatic reticulum may be inactivated when the pyramidal neurons [101]. The estrogen receptor modulator
potential difference across the membrane is increased, thus it tamoxifen has recently been shown to have a particularly
is possible that influx of Cl- across the cell membrane also dramatic potentiating effect on sub-maximal glycine
increases the potential difference across the endoplasmatic responses in cultivated spinal neurons and a 5µM
reticulum making the IP3-receptor more difficult to open concentration caused a 6.6-fold reduction in the glycine EC50
[30]. [102].
There are different isoforms of the α-subunit. Kupffer Glyphosate may also disrupt glycine receptors, driving
cells express the α1-subunit while inflammatory cells contain Ca2+ into the tissues and opening Cl- channels [103], although
a different isoform; the α2-subunit. Differences in the GlyR there do not appear to be any papers in the literature
6 Mini-Reviews in Medicinal Chemistry, 2016, Vol. 16, No. 0 Pérez-Torres et al.
supporting this hypothesis. Strychnine interferes with GlyR MS, including a decrease in blood pressure (BP) and an
activity, and glyphosate may do so in a similar way [104]. increase in high density lipoprotein (HDL) [113].
Glycine supplemented to a sucrose fed rat model of MS
2.2. NMDA Receptor
lowers non-esterified fatty acids (NEFAs) in plasma,
In addition, glycine is also a co-agonist of glutamate that triglycerides (TG), intra-abdominal fat and BP [114].
binds to NMDA. Glycine can bind to the NR1 subunit of the Unpublished results from our laboratory in this same MS
NMDA receptor to potentiate its activation in the dorsal model show that 1% glycine in the drinking water for a
vagal complex. This lowers the secretion of hepatic month, decreases intra-abdominal fat which is associated
triglyceride-rich very low-density lipoproteins by inhibiting with diminished hypertrophic adiposity in MS, and with
hepatic Scd-1 gene expression therefore contributing to reduced circulating TG and total fatty acids in adipocytes.
normalize hypertriglyceridemia [105]. The competitive The precise mechanism by which glycine reverses adipocyte
antagonists for the glycine-binding site in the NMDA hypertrophy remains unknown; however, there might be a
receptor can cause neuroprotection to different extents; direct association between adipocyte size and amount of TG.
implying that the NMDA receptor may be engaged in Reduced hypertrophy by the glycine treatment could be due
glycine-induced cytoprotection [35]. to reduced total fatty acids in adipocytes that are indicative
of the total amount of stored TG (Fig. 1). In obese C57BL-6J
NMDA receptors respond to the simultaneous presence mice, a scallop protein diet supplement with taurine and
of glutamate and glycine [106]. Studies on rats exposed to glycine, prevented obesity and improved plasma lipid profile
glyphosate have shown that its mechanism of action in the [115].
hippocampus is over-stimulation of NMDA receptors [107],
likely due to glyphosate's chelation of manganese interfering The increase in circulating inflammatory cytokines
with glutamate recycling [108] coordinated with its direct secreted by adipocytes in obesity such as TNF-α,
action as a glycine mimetic. interleukins (IL)-6, interferon (IFN)-γ and IL-1B, reduces
skeletal muscle protein synthesis and increase intracellular
2.3. GlyT1 and GlyT2 Ca2+ concentration triggering pathways that degrade
muscular tissue. These characteristics are also present in
Other glycine transporters, known as GlyT1 and GlyT2, mice with cancer cachexia. However, subcutaneous
which are specific and dependent on Na+ and Cl- and which injections of 1g/Kg of glycine for 21 days attenuated tumor
are present in the plasma membrane of the nerve terminals, growth and the loss of fat mass and prevented the loss of
glia, pancreas, liver and retinal Muller cells have also been tumor free body mass by reducing the oxidative and
described [109, 110]. GlyT1 and GlyT2 transport glycine by inflammatory burden and expression of genes associated
a high affinity active electrogenic mechanism coupled to the with muscle protein breakdown in cancer cachexia [116].
electrochemical gradient of Na+ and Cl- using a 93 kDa
subunit of the cytoplasmic anchoring protein gephyrin [85]. The treatment with 10 mM glycine decreased the mRNA
The GLYT system is unique among glycine transporters in levels of IL-6, TNF-α and resistin and it increased the
that it is highly substrate- specific and has a high affinity for mRNA levels of adiponectin in differentiated 3T3-L1
glycine. Two genes that encode for the system GLYT-like adipocites. Pretreatment with glycine for 30 min in
activity have been identified, and both are members of the differentiated 3T3-L1 adipocytes before stimulation with
Na+- and Cl- -dependent neurotransmitter transporter family, TNF-α, reduced the amount of active nuclear factor kappa B
SLC6. The gene encoding for GLYT1 is SLC6A9 and the (NF-κB). It is therefore possible that glycine might interfere
gene encoding for GLT2 is SLC6A5 [40]. GLYT1 is with the phosphorylation or ubiquitin-dependent degradation
localized predominantly at the basolateral membrane of of inhibitor of nuclear factor kB (IκBs) and that it could
enterocytes and its primary function is to import glycine into accelerate the removal of the active forms of NF-κB from the
the cell, suggesting a role in meeting essential requirements nucleus, or that a combination of these mechanisms could
of the enterocyte, rather than in nutrient absortion [111]. take place. Glycine could be activating inhibitors of NF-κB
Sarcosine is an endogenous amino acid that is a competitive (IκB-α, IκB-β and IκB-ε) in differentiated 3T3-L1 adipocytes
inhibitor of the type I glycine transporter (GlyT1), and a since it suppresses TNF-α dependent NF-κB activation and,
NMDA receptor co-agonist [112]. Sarcosine is a breakdown as a result, it might decrease the expression of NF-κB-
product of glyphosate, but glyphosate might itself behave dependent genes, such as the pro-inflammatory adipokines
similarly to sarcosine [112]. This deserves further study. TNF-α and IL-6 [117].
In obese mice generated by treatment with monosodium
3. EFFECT OF GLYCINE ON DYSLIPIDEMIA, glutamate (MSG/Ob) with glycine added in tap water (0.1 g/
OBESITY AND METABOLIC SYNDROME Kg) for 60 days and compared to lean mice, glycine clearly
Evidence has accumulated showing that glycine protects increased fat tissue peroxisome proliferator-activated
against a variety of diseases in experimental models of receptor (PPAR)-γ expression in lean but not in MSG/Ob
dyslipidemia, obesity and metabolic syndrome (MS). A mice. The PPAR-γ and PPAR-α liver expression was
study comparing 30 subjects with MS plus placebo against repressed in both groups of mice, while the expression of
30 subjects with MS plus 15/day glycine supplement for 3 PPAR-δ decreased only in lean mice. Glycine treatment also
months, showed that glycine can modify the activity of some suppressed the expression of uncoupling protein (UCP)-2,
of the parameters established by NCEP/ATP III to diagnose TNF-α and IL-6 in lean mice, and increased adiponectin and
insulin serum levels. Therefore, glycine regulates the
Beneficial Effects of the Amino Acid Glycine Mini-Reviews in Medicinal Chemistry, 2016, Vol. 16, No. 0 7
Fig. (1). Photomicrographs of visceral white adipose tissue of the experimental groups A (Control), B (Metabolic syndrome), C (Metabolic
syndrome plus glycine) and D (Metabolic syndrome plus glycine and strychinine. Abbreviations: N = nucleus, M = cellular membrane,
Staining. Hematoxylin-Eosin to 20x.
membrane GlyR without stimulating insulin secretion. The decrease protein content, reduce the antioxidant systems
threshold of glycine to stimulate glucagon release is 0.2 mM such as glutathione (GSH) and super oxide dismutase
in plasma [130]. Studies in vivo in human subjects have (SOD), and decrease the activity of the polyol pathway in the
shown that oral or intravenous administration of glycine lenses [140]. In streptozotocin diabetic rats, glycine 1% in
stimulates a rise in plasma glucagon levels but not those of the drinking water induced a significant decrease of TG and
insulin [128]. Another study showed that in 73 old adults inhibited non-enzymatic glycation of ocular lens proteins
(age range, 70-85 year) glycine was the only metabolite [135].
to reach statistical significance in association with
In type II diabetes patients using 20g/day of glycine for 6
subcutaneous adipose tissue (SCAT), thereby identifying
months, TC fractions showed a significant decrease of total
glycine as a HOMA-IR associated marker of multiple
TC and HDL increase in males, without changes in low
adipose-containing compartments [131].
density lipoprotein (LDL). In contrast, in females it induced
Furthermore, glycine might prevent IR and the associated a significant decrease in LDL and elevated HDL without
inflammatory disease by reduced serum leptin concentration, changes in TC [141]. When intracellular GSH concentrations
elevating the production of insulin and ameliorating IR were measured in diabetic patients, diabetic patients plus
[132]. In IR obese patients there are changes in plasma glycine and non-diabetic control subjects a restoration of the
amino acid concentrations. decreased GSH synthesis of diabetic patients was observed
when the dietary supplementation of this amino acid was
5. EFFECTS OF GLYCINE ON DIABETES administered [142].
Many years ago, it was reported that glycine (40-50g),
6. EFFECT OF GLYCINE ON THE VASCULAR
given orally, resulted in a moderate reduction in blood
SYSTEM, HYPERTENSION AND ISCHEMIA-
glucose concentrations in healthy and diabetic adults (102 to
REPERFUSION
72 mg/dL and 256 to 161 mg/dL respectively). Other studies
reported no effect on blood glucose concentration in fasting Evidence has accumulated showing that glycine protects
subjects. However, intravenously administered glycine against a variety of diseases in experimental models of
stimulates glucagon secretion in dogs and could alter glucose hypertension and ischemia-reperfusion. This amino acid,
concentrations [133]. when supplemented to a low protein diet of rat dams during
pregnancy, also has a beneficial effect on BP in the offspring
The glucose excess in type 2 diabetes alters the
[123].
functionality of the structural membrane and of transport
proteins due to non-enzymatic glycation. Oxidative glycation Glycine is required for a number of critical metabolic
induces functional alterations of endothelial cells and pathways, such as the synthesis of the structural proteins
stimulates monocyte-binding to the vascular endothelium collagen and elastin. The perturbation of these pathways
and studies have suggested that administration of glycine might lead to impaired elastin formation in large blood
prevents glycation of proteins and induces lower osmotic vessels such as the aorta, causing changes in the elastic
damage [134]. Non-enzymatic glycation involves the properties and contributing to the development of
condensation reaction of the carbonyl group of sugar hypertension [143]. Unpublished data from our laboratory
aldehydes with the NH2-terminus or free-amino groups of have shown that treatment with 1% glycine tends to increase
proteins. The initial product of this reaction is called a Schiff the amount of elastic fibers in rat aortic rings with MS (Fig. 2).
base [135], which spontaneously rearranges itself into the This result suggests that glycine promotes the synthesis of
Amadori products. These compounds are relatively stable elastic fibers that contribute to vasodilation associated with a
intermediates that can undergo a series of complex reactions decrease in blood pressure in aortic rings in the MS rats
that may lead to the formation of advanced glycation end characterized by altered vasoreactivity.
products (AGEs) [136]. Cataracts in the diabetic patient are
the consequence of the precipitation of non-enzymatic In tumors, angiogenesis is a multistage process that
involves release of angiogenic factors from several cell types
glycated crystalline proteins and glycation of the retinal
including endothelial cells that control proliferation and
vessels. Glycation causes the conformational change,
migration of other cells and synthesis of the vascular
aggregation, and formation of insoluble materials. Glycine
basement membrane. Proliferation of endothelial cells is a
decreased cataract genesis having a protein-antiglycating
key step in the process by which new blood vessels grow
potential effect and it acts as a glucose scavenger by self-
glycation [137]. Clinical studies have shown that glycine from established ones, and glycine may inhibit angiogenesis
by preventing endothelial cell proliferation and therefore
lowers glycated haemoglobin (HBA) in patients with type 2
block the increase of tumor size. Glycine inhibits agonist-
diabetes [138] and suggests that glycine may act upon TG
induced increases in Ca2+, in endothelial cells by activating a
and insulin, slowing down their biosynthesis.
Cl- channel, and since regulation of the cell cycle is Ca2+
Aqueous humor in the diabetic retinopathy contains AGE dependent, glycine may inhibit endothelial cell proliferation
products and in streptozotocin diabetic rats 1 % w/v glycine via inhibition of Ca2+ signaling [144].
attenuates the percentage of opacity of the lens and
Vascular endothelial growth factor (VEGF) is one of the
microaneurysms in the eyes [139]. In another study in
key factors for the survival and proliferation of endothelial
streptozotocin-induced diabetic rats, the administration of
cells. Deprivation of VEGF induces apoptosis in endothelial
1% of glycine in drinking water for three months ad libitum
cells. VEGF increases the expression of the anti-apoptotic
decreased the cataracts by decreasing HBA1c. AGEs
Beneficial Effects of the Amino Acid Glycine Mini-Reviews in Medicinal Chemistry, 2016, Vol. 16, No. 0 9
and CAT which are key enzymes in the regulation of during hypoxia is likely to have severe consequences for cell
superoxide anion release from the cell [162]. function and could initiate a cascade of reactions resulting in
cell death.
10. EFFECTS OF GLYCINE ON THE KIDNEY
Experimentally, the addition of glycine 1% to the
Supplementation with the non-essential amino acid drinking water in a MS model showed that glycine
glycine, in isolated rat and rabbit proximal tubules, significantly decreases albuminuria and improves creatinine
significantly reduces the damage caused by hypoxia; it also clearance which suggests that glycine is able to protect from
inhibits protease activity, ATP depletion and cyclosporine A renal hemodynamic changes. Glycine treatment normalized
nephrotoxicity [154]. In the isolated perfused kidney, glycine the AA concentration and decreased the expression of the
diminishes the deterioration of renal function [163], and the cyclooxigenase (COX) isoforms and prostaglandins levels in
inhibition of sodium proximal re-absorption. In addition, the kidney in this model [152]. Other results suggest that
glycine induces a decrease in renal vascular resistance and a glycine can modulate the expression and activity of COX
consequent increase in glomerular filtration rate (GFR) isoforms, favoring an anti-inflammatory effect and
[164]. Glycine causes renal vasodilation and protects decreasing the vasoconstriction of renal arteries, which
cultures of proximal tubules from hypoxic injury [165]. In contributes to protect renal function and decrease BP. In
isolated perfused rat kidneys, the addition of 2 mmol/L-1 addition, dietary glycine blocks the increase in serum
glycine prevented severe morphological injury caused by creatinine and decreases glomerular filtration rates caused by
hypoxia to tubular cells in the medullary thick ascending cyclosporine A. 5% glycine protects the kidney against
limb [166]. In Isolated rat and rabbit proximal tubules, injury induced by brief ischemia, in part, by reducing ROS
glycine strongly reduced the damage caused by various production early after reperfusion as well as chronic hypoxia
injurious processes such as hypoxia, ouabain, metabolic in the outer medulla during recovery [169]. An infusion of
inhibitors, ionomycin and phosphate depletion [167], and glycine (1mmol per 100g body weight per hour for 75
inhibits sodium reabsorption in the proximal tubule [164]. minutes) ameliorates tubular injury and renal dysfunction in
rats treated with cisplatin [170]. Glycine in the diet (5%)
In Madin-Darby canine kidney cells with ATP depletion, shows a protective effect in vivo against renal ischemia
glycine acting through GlyR showed cytoprotection and it followed by reperfusion [169].
induced extracellular signal regulated kinase (ERK)-1/2 and
serine-threonine protein kinase (AKT) in the ATP-depleted
11. EFFECTS OF GLYCINE ON THE LIVER
cells. This may constitute the signaling pathways to regulate
the protective effect glycine on the permeability of the cell All cellular proteins are potential substrates for
membrane. Inhibition of ERK-1/2 or AKT influences cell proteolytic enzymes and an increase in protease activity
apoptosis under ATP depletion and glycine could inhibit could result in partially degraded cell structures. Inhibition
autophagy by increasing the level of phosphorylated ERK1 of proteases could be part of the protective effect of glycine,
via ERK1/2 activation and p38 depression under ATP- since it inhibits protease activity. In recent studies, a role of
depletion [86]. proteolytic enzymes in hypoxia-induced cell injury has been
suggested. Glycine improves the survival rate in rat liver
The cytoprotective mechanism of glycine makes it a
transplantation [2]. In livers stored in ice, glycine inhibited
potential protector against impairment of hypoxia and/or metallo and aspartate protease activity [57]. Glycine inhibits
mitochondria toxicity [86]. Glycine enables ATP-depleted
nonlysosomal Ca2+-dependent proteases and protects
cells to maintain structural integrity despite complete
hepatocytes against anoxic damage.
disruption of ion homeostasis. Protected by glycine, ATP-
depleted cells can sustain surprisingly high elevations of Glycine could protect livers in situ from reperfusion
intracellular-free Ca2+, yet survive and subsequently damage by minimizing LPO and could stabilize the cell
proliferate. These actions may account, at least in part, for membrane by inhibiting PLA2 leading to a reduction of AA
the in vivo beneficial effects of glycine in organ and eicosanoids which influence hepatic microcirculation
preservation, transplantation, and septic shock [168]. [7]. Hepatic injury and the subsequent repair and
Glycine provided during ATP depletion completely blocked inflammatory process increase fibrosis and glycine
the development of pores in the membranes. The actions of attenuates liver fibrosis caused by carbon tetrachloride.
glycine can be mimicked by cross-linking of plasma Attenuation of fibrosis is associated with decreased collagen
membrane proteins with a cell-impermeant cross-linker, 3,3′- synthesis rather than increased collagen degradation [171].
dithiobis-sulfosuccinimidylpropionate [16].
Glycine inhibits activation of stellate cells and synthesis
Glycine (10 mM) restores the decrease in calpain activity of transforming growth factor beta (TGFβ) and these effects
in renal proximal tubules [57]. The small subunit of calpain, can be mimicked by removal of Kupffer cells with
a protein participating in cell differentiation, in long-term gadolinium chloride [171]. In liver injury induced by bile
memory, in the regulation of cell adhesion and in signaling duct ligation and vitamin D deficiency, glycine increases bile
pathways, contains a glycine-rich strand, which is important production, it attenuates oxidative stress, apoptosis and
for membrane association. Many physiologically important
vitamin D deficiency [172]. Glycine supplementation (0.6
proteins are candidate substrates for calpain, such as
g/Kg body weight) in rats with alcohol induced
cytoskeletal proteins, protein kinase C and A,
hepatotoxicity, significantly lowered the activities of serum
phospholipases, protein phosphatases, and the plasma
aspartate transaminase (AST), alanine transaminase (ALT),
membrane Ca2+-ATPase. Therefore, activation of calpain
12 Mini-Reviews in Medicinal Chemistry, 2016, Vol. 16, No. 0 Pérez-Torres et al.
alkaline phosphatases (ALP) and γ-glutamyl transpeptidase to import glycine into the cell, suggesting a role in meeting
(GGT) and normalized the liver and brain fatty acid essential requirements of the enterocyte, rather than in
composition compared with untreated alcohol-fed rats [173]. nutrient absorption [111].
In a model of non-alcoholic steatohepatitis induced by a The role of GLYT1 in the cytoprotective effect of glycine
diet deficient in methionine and choline, glycine against oxidative stress was investigated in human intestinal
supplementation (5 g/100 g) reverted the increase in body epithelial cells. Glycine protected cells against the oxidative
weight gain, elevated plasma and hepatic lipids, improved agent ter-butyhydroperoxide and reduced the intracellular
liver function test, and restored tumor markers and the concentrations of reactive oxygen species [40]. Orally
disturbance in the expression of hepatic fatty acid transport administred glycine competes with glucose for absorption
proteins. In rats with liver injury caused by hemorrhagic and stimulates the secretion, either directly or indirectly of a
shock, a diet including 5% of glycine protected against liver glucagon-like peptide1 (GLP1) gut hormone. This hormone
injury and death caused by hemorrhagic shock, preventing potentiates or is additive with the effect of insulin in
oxidative stress and blocking posttranslational inhibition of stimulating the removal of glucose from the circulation
antioxidant enzymes, TNF-α production, and iNOS [136]. Glycine also inhibited the effect of glucagon on
overexpresion [162]. endogenous glucose production. The effect of ingested
glycine on the postprandial glucose concentration may be
Glycine reduced hepatic inflammation and necrosis in important therapeutically in persons with type 2 diabetes [3].
alcoholic liver injury by inhibition of TNF-α production by
activated Kupffer cells. In these animals, total hepatic TG In the intestine, glycine protects from damage caused
production was increased by stimulated peripheral lipolysis during mesenteric ischemia by inhibition of apoptosis [136].
resulting in an increase in NEFAs, leading to increased Glycine also protected against intestinal injury due to
delivery of lipid to the liver where it was re-esterified. A inhibition of TNF-α in chemical models of colitis induced by
decrease in lipoprotein lipase activity by TNF-α is dextran sulfate sodium or trinitrobenzene sulfonic acid. Both
responsible for decreased clearance of TG-rich lipoproteins, models involve epithelial irritation and damage prior to
such as very low density lipoproteins, leading to activation of different immune cell populations [176].
hyperlipidemia [43]. Glycine also decreased acid secretion caused by pylorus-
ligation and protected against experimental gastric lesions
The pretreatment with 5% glycine in chow for 5 days in induced by hypothermic restraint stress, indomethacin and
male wistar rats decreased tissue injury after 90% partial necrotizing agents including 80% ethanol, 0.2 M sodium
hepatotectomy evidenced by decreased transaminase release, hydroperoxide and 0.6 M hydrochloric acid in a dose-
improved histology and parameters of liver function. Glycine dependent manner [177].
pretreatments did not have adverse effects on liver
regeneration. In addition, glycine improved the hepatic In rats with mesenteric ischemia/reperfusion injury
microcirculation and reduced injury in a low-flow, reflow glycine infused at a dose of either 0.5, 0.75, or 1 mg/g
model in the perfused liver [32]. infused at the rate of 0.01 ml/g/h during the reperfusion
period showed that intestinal cell viability was preserved and
In another study done in Balb/c mice in which the physiologic function of small bowel was significantly
pretreatment with glycine intraperitoneally was given 24 h better than in the saline-treated animals [61].
before and 1h after the intraperitoneal injection of LPS/D-
Gal showed that it protected against liver damage and that
13. CONCLUSIONS
aminotransferase levels decreased to 10% associated with
significant improvement in the degree of necrosis, Glycine protects against oxidative stress caused by a
inflammation, TNF-α levels and an increase in the serum wide variety of chemicals, drugs and toxicants at the cellular
levels of the anti-inflammatory cytokine IL-10 [26]. or organ level in the liver, kidney, intestine, and vascular
system. Glycine is abundant in the diet, being a component
Cytoprotection of liver cells by glycine has been
released during protein digestion, and is considered to be
observed in the absence of Cl- and calcium ions [174]. Other
non-toxic even in high doses. The herbal pesticide
studies showed that glycine prevents entry of sodium and the
glyphosate might alter glycine homeostasis by binding to its
non-physiological cations cobalt and nickel into hypoxic
receptors. Although at high-doses, glycine may cause toxic
hepatocytes and indicated that the protective effect of
effects, further studies are needed to investigate the safe
glycine does not require the presence of Cl-. This suggests
range that may improve disease conditions and to test the
that glycine can inhibit ion flux through nonspecific leaks
diverse routes of its administration.
[174]. Furthermore, dietary glycine blunted the growth of
B16 melanoma tumors in mice and the development in liver
LIST OF ABBREVIATIONS
tumors caused by the nongenotoxic carcinogen and
peroxisome proliferator WY-14643 in rats [175]. AA = Arachinonic acid
12. EFFECTS OF GLYCINE ON THE INTESTINE AGES = Advanced glycation end products
[10] Weinberg, J.M.; Davis, J.A.; Abarzua, M.; Rajan, T. Cytoprotective [31] Li, X.; Bradford, B.U.; Wheeler, M.D.; Stimpson, S.A.; Pink,
effects of glycine and glutathione against hypoxic injury to renal H.M.; Brodie, T.A.; Schwab J.H.; Thurman R.G. Dietary glycine
tubules. J. Clin. Invest., 1987, 80(5), 1446-1454. prevents peptidoglycan polysaccharide-induced reactive arthritis in
[11] Weinberg, J.M.; Davis, J.A.; Abarzua, M.; Kiani, T. Relationship the rat: role for glycine-gated chloride channel. Infect. Immun.,
between cell adenosine triphosphate and glutathione content and 2001, 69(9), 5883-5891.
protection by glycine against hypoxic proximal tubule cell injury. [32] Bruck, R.; Wardi, J.; Aeed, H.; Avni, Y.; Shirin, H.; Avinoach, I.;
J. Lab. Clin. Med., 1989, 113(5), 612-622. Shahmurov, M.; Hershkoviz, R. Glycine modulates cytokine
[12] Weinberg, J.M.; Venkatachalam, M.A.; Garzo-Quintero, R.; secretion, inhibits hepatic damage and improves survival in a
Roeser, N.F.; Davis, J.A. Structural requirements for protection by model of endotoxemia in mice. Liver Int., 2003, 23(4), 276-282.
small amino acids against hypoxic injury in kidney proximal [33] Yamashina, S.; Konno, A.; Wheeler, M.D.; Rusyn, I.; Rusyn, E.V.;
tubules. FASEB J., 1990, 4(15), 3347-3354. Cox, A.D.; Thurman, R.G. Endothelial cells contain a glycine-
[13] Weinberg, J.M.; Venkatachalam, M.A.; Goldberg, H.; Roeser, gated chloride channel. Nutr. Cancer, 2001, 40(2), 197-204.
N.F.; Davis, J.A. Modulation by Gly, Ca, and acidosis of injury- [34] Weinberg, J.M.; Varani, J.; Johnson, K.J.; Roeser, N.F.; Dame,
associated unesterified fatty acid accumulation in proximal tubule M.K.; Davis, J.A.; Venkatachalam, M.A. Protection of human
cells. Am. J. Physiol., 1995, 268(1 Pt 2) F110-F121. umbilical vein endothelial cells by glycine and structurally similar
[14] Mandel, L.J.; Schnellmann, R.G.; Jacobs W.R. Intracellular amino acids against calcium and hydrogen peroxide-induced lethal
glutathione in the protection from anoxic injury in renal proximal cell injury. Am. J. Pathol., 1992, 140(2) 457-471.
tubules. J. Clin. Invest., 1990, 85(2), 316-324. [35] Pan, C.; Bai, X.; Fan, L.; Ji, Y.; Li, X.; Chen, Q. Cytoprotection by
[15] Paller, M.S.; Patten, M. Protective effects of glutathione, glycine, glycine against ATP-depletion-induced injury is mediated by
or alanine in an in vitro model of renal anoxia. J. Am. Soc. glycine receptor in renal cells. Biochem. J., 2005, 390(Pt2), 447-
Nephrol., 1992, 2(8), 1338-1344. 453
[16] Tijsen, M.J.; Peters, S.M.; Bindels, R.J.; van Os, C.H.; Wetzels, [36] Zhang, K.; Weinberg, J.M.; Venkatachalam, M.A.; Dong, Z.
J.F. Glycine protection against hypoxic injury in isolated rat Glycine protection of PC-12 cells against injury by ATP-depletion.
proximal tubules: the role of proteases. Nephrol. Dial Transplant., Neurochem. Res., 2003, 28(6), 893-901.
1997, 12(12), 2549-2556. [37] Nishimura, Y.; Romer, L.H.; Lemasters, J.J. Mitochondrial
[17] Moran, J.H.; Schnellmann, R.G. Diverse cytoprotectants prevent dysfunction and cytoskeletal disruption during chemical hypoxia to
cell lysis and promote recovery of respiration and ion transport. cultured rat hepatic sinusoidal endothelial cells: the pH paradox
Biochem. Biophys. Res. Commun., 1997, 234(1), 275-277. and cytoprotection by glucose, acidotic pH, and glycine.
[18] Wetzels, J.F.; Wang, X.; Gengaro, P.E.; Nemenoff, R.A.; Burke, Hepatology, 1998, 27(4), 1039-1049.
T.J; Schrier, R.W. Glycine protection against hypoxic but not [38] Zhao, P.; Qian, H.; Xia, Y. GABA and glycine are protective to
phospholipase A2-induced injury in rat proximal tubules. Am. J. mature but toxic to immature rat cortical neurons under hypoxia.
Physiol., 1993, 264(1 Pt 2), F94-F99. Eur. J. Neurosci., 2005, 22(2), 289-300.
[19] Aleo, M.D.; Schnellmann, R.G. The neurotoxicants strychnine and [39] Ruiz-Meana, M.; Pina, P.; Garcia-Dorado, D; Rodríguez-Sinovas,
bicuculline protect renal proximal tubules from mitochondrial A.; Barba, I.; Miró-Casas, E.; Mirabet, M.; Soler-Soler, J. Glycine
inhibitor-induced cell death. Life Sci., 1992, 51(23), 1783-1787. protects cardiomyocytes against lethal reoxygenation injury by
[20] Dickson, R.C.; Bronk, S.F.; Gores, G.J. Glycine cytoprotection inhibiting mitochondrial permeability transition. J. Physiol., 2004,
during lethal hepatocellular injury from adenosine triphosphate 558(Pt 3), 873-882.
depletion. Gastroenterology., 1992, 102(6), 2098-2107. [40] Howard, A.; Tahir, I.; Javed, S.; Waring, S.M.; Ford, D.; Hirst,
[21] Petrat, F.; Boengler, K.; Schulz, R.; de Groot, H. Glycine, a simple B.H. Glycine transporter GLYT1 is essential for glycine mediated
physiological compound protecting by yet puzzling mechanism(s) protection of human intestinal epithelial cells against oxidative
against ischaemia-reperfusion injury: current knowledge. Br. J. damage. J. Physiol., 2010, 588(Pt 6), 995-1009.
Pharmacol., 2012, 165(7), 2059-2072. [41] Deters, M.; Strubelt, O.; Younes,M. Protection by glycine against
[22] Qian, T.; Nieminen, A.L.; Herman, B.; Lemasters, J.J. hypoxia-reoxygenation induced hepatic injury. Res. Commun. Mol.
Mitochondrial permeability transition in pH-dependent reperfusion Pathol. Pharmacol., 1997, 97, 199-213.
injury to rat hepatocytes. Am. J. Physiol., 1997, 273(6 Pt 1), [42] Deters, M.; Siegers, C.P.; Strubelt, O. Influence of glycine on the
C1783-C1792. damage induced in isolated perfused rat liver by five hepatotoxic
[23] Marsh, D.C.; Vreugdenhil, P.K.; Mack, V.E.; Belzer, F.O.; agents. Toxicology, 1998, 128(1), 63-72.
Southard, J.H. Glycine protects hepatocytes from injury caused by [43] Zhong, Z.; Jones, S.; Thurman, R.G. Glycine minimizes
anoxia, cold ischemia and mitochondrial inhibitors, but not injury reperfusion injury in a low-flow, reflow liver perfusion model in
caused by calcium ionophores or oxidative stress. Hepatology, the rat. Am. J. Physiol., 1996, 270(2 Pt 1), G332-G338.
1993, 17(1), 91-98. [44] Qi, R.B.; Zhang, J.Y.; Lu, D.X.; Wang, H.D.; Wang, H.H.; Li, C.J.
[24] Marsh, D.C.; Hjelmhaug, J.A.; Vreugdenhil, P.K.; Belzer, F.O.; Glycine receptors contribute to cytoprotection of glycine in
Southard, J.H. Glycine prevention of cold ischemic injury in myocardial cells. Chin. Med. J. (Engl)., 2007, 120(10), 915-921.
isolated hepatocytes. Cryobiology, 1991, 28(1), 105-109. [45] den Butter, G.; Lindell, S.L.; Sumimoto, R.; Schilling, M.K.;
[25] Carini, R.; Bellomo, G.; de Cesaris, M.G.; Albano, E. Glycine Southard, J.H.; Belzer, F.O. Effect of glycine in dog and rat liver
protects against hepatocyte killing by KCN or hypoxia by transplantation. Transplantation, 1993, 56(4), 817-822.
preventing intracellular Na+ overload in the rat. Hepatology, 1997, [46] den Butter, G.; Marsh, D.C.; Lindell, S.L.; Belzer, F.O.; Southard,
26(1), 107-112. J.H. Effect of glycine on isolated, perfused rabbit livers following
[26] Frank, A.; Rauen, U.; de Groot, H. Protection by glycine against 48-hour preservation in University of Wisconsin solution without
hypoxic injury of rat hepatocytes: inhibition of ion fluxes through glutathione. Transpl. Int., 1994, 7(3), 195-200.
nonspecific leaks. J. Hepatol., 2000, 32(1), 58-66. [47] Currin, R.T.; Caldwell-Kenkel, J.C.; Lichtman, S.N.; Bachmann,
[27] Ikejima, K.; Qu, W.; Stachlewitz, R.F.; Thurman, R.G. Kupffer S.; Takei, Y.; Kawano, S.; Thurman, R.G.; Lemasters, J.J.
cells contain a glycine-gated chloride channel. Am. J. Physiol., Protection by Carolina rinse solution, acidotic pH, and glycine
1997, 272(6 Pt 1), G1581-G1586. against lethal reperfusion injury to sinusoidal endothelial cells of
[28] Froh, M.; Thurman, R.G.; Wheeler, M.D. Molecular evidence for a rat livers stored for transplantation. Transplantation, 1996, 62(11),
glycine-gated chloride channel in macrophages and leukocytes. 1549-1558.
Am. J. Physiol. Gastrointest. Liver Physiol., 2002, 283(4), 856-863. [48] Mangino, M.J.; Murphy, M.K.; Grabau, G.G.; Anderson, C.B.
[29] Stachlewitz, R.F.; Li, X.; Smith, S.; Bunzendahl, H.; Graves, L.M.; Protective effects of glycine during hypothermic renal ischemia-
Thurman, R.G. Glycine inhibits growth of T lymphocytes by an IL- reperfusion injury. Am. J. Physiol., 1991, 261(5 Pt 2), F841-F848.
2-independent mechanism. J. Immunol., 2000, 164(1), 176-182. [49] Omasa, M.; Fukuse, T.; Toyokuni, S.; Mizutani, Y.; Yoshida, H.;
[30] Wheeler, M.; Stachlewitz, R.F.; Yamashina, S.; Ikejima, K.; Ikeyama, K.; Hasegawa, S.; Wada, H. Glycine ameliorates lung
Morrow, A.L.; Thurman, R.G. Glycine-gated chloride channels in reperfusion injury after cold preservation in an ex vivo rat lung
neutrophils attenuate calcium influx and superoxide production. model. Transplantation, 2003, 75(5), 591-598.
FASEB J., 2000, 14(3), 476-484.
Beneficial Effects of the Amino Acid Glycine Mini-Reviews in Medicinal Chemistry, 2016, Vol. 16, No. 0 15
[50] Mangino, J.E.; Kotadia, B.; Mangino, M.J. Characterization of [67] Ascher, E.; Hanson, J.N.; Cheng, W.; Hingorani, A.; Scheinman M.
hypothermic intestinal ischemia-reperfusion injury in dogs. Effects Glycine preserves function and decreases necrosis in skeletal
of glycine. Transplantation, 1996, 62(2), 173-178. muscle undergoing ischemia and reperfusion injury. Surgery, 2001,
[51] Gohrbandt, B.; Fischer, S.; Warnecke, G.; Avsar, M.; Sommer, 129(2), 231-235.
S.P.; Haverich, A.; Strueber, M. Glycine intravenous donor [68] Warnecke, G.; Schulze, B.; Steinkamp, T.; Haverich, A.; Klima, U.
preconditioning is superior to glycine supplementation to low- Glycine application and right heart function in a porcine heart
potassium dextran flush preservation and improves graft function in transplantation model. Transpl. Int., 2006, 19(3), 218-224.
a large animal lung transplantation model after 24 hours of cold [69] Wang, G.; Zhao, M.; Wang, E.H. Effects of glycine and
ischemia. J. Thorac. Cardiovasc. Surg., 2006, 131(3), 724-729. methylprednisolone on hemorrhagic shock in rats. Chin. Med. J.
[52] Duenschede, F.; Westermann, S.; Riegler, N.; Miesner, I.; Erbes, (Engl)., 2004, 117(9), 13334-1341.
K.; Ewald, P.; Kircher, A.; Schaefer, H.; Schneider, J.; Schad, A.; [70] Evins, A.E.; Fitzgerald, S.M.; Wine, L.; Rosselli, R.; Goff, D.C.
Dutkowski, P.; Kiemer, A.K.; Junginger, T. Different protection Placebo-controlled trial of glycine added to clozapine in
mechanisms after pretreatment with glycine or alpha-lipoic acid in schizophrenia. Am. J. Psychiatry, 2000, 157(5), 826-828.
a rat model of warm hepatic ischemia. Eur. Surg. Res., 2006, 38(6), [71] Heresco-Levy, U.; Javitt, D.C.; Ermilov, M.; Mordel, C.; Horowitz,
503-512. A.; Kelly, D. Double-blind, placebo-controlled, crossover trial of
[53] Rentsch, M.; Puellmann, K.; Sirek, S.; Iesalnieks, I.; Kienle, K.; glycine adjuvant therapy for treatment-resistant schizophrenia. Br.
Mueller, T.; Bolder, U.; Geissler, E.; Jauch, K.W.; Beham, A. J. Psychiatry, 1996, 169(5), 610-617.
Benefit of Kupffer cell modulation with glycine versus Kupffer cell [72] Leung, S.; Croft, R.J.; O'Neill, B.V.; Nathan, P.J. Acute high-dose
depletion after liver transplantation in the rat: effects on glycine attenuates mismatch negativity (MMN) in healthy human
postischemic reperfusion injury, apoptotic cell death graft controls. Psychopharmacology (Berl)., 2008, 196(3), 451-460.
regeneration and survival. Transpl. Int., 2005, 18 (9), 1079-1089. [73] Arora, A.S.; Nichols, J.C.; DeBernardi, M.; Steers, J.L.; Krom,
[54] Liu, Z.J.; Yan, L.N.; Li, S.W.; You, H.B.; Gong, J.P. Glycine R.A.; Gores, G.J. Glycine rinse protects against liver injury during
blunts transplantative liver ischemia-reperfusion injury by transplantation. Transplant Proc., 1999, 31(1-2), 505-506.
downregulating interleukin 1 receptor associated kinase-4. Acta [74] Gusev, E.I.; Skvortsova, V.I.; Dambinova, S.A.; Raevskiy, K.S.;
Pharmacol. Sin., 2006, 27(11), 1479-1486. Alekseev, A.A.; Bashkatova, V.G.; Kovalenko, A.V.; Kudrin, V.S.;
[55] Ikejima, K.; Iimuro, Y.; Forman, D.T.; Thurman, R.G. A diet Yakovleva, E.V. Neuroprotective effects of glycine for therapy of
containing glycine improves survival in endotoxin shock in the rat. acute ischaemic stroke. Cerebrovasc. Dis., 2000, 10(1), 49-60.
Am. J. Physiol., 1996, 271(1 Pt 1), G97-G103. [75] Holmes, R.P.; Assimos, D.G. Glyoxylate synthesis, and its
[56] Pérez-Torres, I.; Ibarra, B.; Soria-Castro, E.; Torrico-Lavayen, R.; modulation and influence on oxalate synthesis. J. Urol., 1998,
Pavón, N.; Diaz-Diaz, E.; Flores, P.; Infante, O.; Baños, G. Effect 160(5), 1617-1624.
of glycine on the cyclooxygenase pathway of the kidney [76] Kearney, P.C.; Kaufman, D.D.; editors. Herbicides Chemistry:
arachidonic acid metabolism in a rat model of metabolic syndrome. Degradation and Mode of Action. CRC Press: USA, 1988.
Can. J. Physiol. Pharmacol., 2011, 89, 1-12. [77] Cebeci, O.; Budak, H. Global expression patterns of three Festuca
[57] Yin, M.; Zhong, Z.; Connor, H.D.; Bunzendahl, H.; Finn, W.F.; species exposed to different doses of glyphosate using the
Rusyn, I.; Li, X.; Raleigh, J.A.; Mason, R.P.; Thurman, R.G. affymetrix genechip wheat genome array. Comp Funct Genomics,
Protective effect of glycine on renal injury induced by ischemia- 2009, 2009, 505701.
reperfusion in vivo. Am. J. Physiol. Renal Physiol., 2002, 282(3), [78] Cole, D.J. Mode of action of glyphosate - A literature analysis. In:
F417-F423. The herbicide glyphosate. Grossbard E.; Atkison D., Editors;
[58] Thomsen, K.; Nielsen, C.B.; Flyvbjerg, A. Effects of glycine on London: Butterworths, 1985, 48‐74.
glomerular filtration rate and segmental tubular handling of sodium [79] Zaidi, A.; Khan, M.S.; Rizvi, P.Q. Effect of herbicides on growth,
in conscious rats. Clin. Exp. Pharmacol. Physiol., 2002, 29(5-6), nodulation and nitrogen content of greengram. Agron Sustain Dev.,
449-454. 2005, 25(4), 497-504.
[59] den Butter, G.; Schilling, M.K.; Lindell, S.L.; Gandolf, D.; [80] Baggish, M.S.; Brill, A.I.; Rosenweig, B.A.; Barbot, J.E.; Indman,
Southard, J.H.; Belzer, F.O. Effect of glutathione and glycine in P.D. Fatal acute glycine and sorbitol toxicity during operative
kidney preservation. Transplant Proc., 1993, 25(1 Pt 2), 1633- 4. hysteroscopy. J Gynecol Surg., 1993, 9(3), 137-143.
[60] Iijima, S.; Shou, .J; Naama, H.; Calvano, S.E.; Daly, J.M. [81] Olsson, J.; Hahn, R.G. Glycine toxicity after high-dose i.v. infusion
Beneficial effect of enteral glycine in intestinal of 1.5% glycine in the mouse. Br J Anaesth., 1999, 82(2), 250-254.
ischemia/reperfusion injury. J. Gastrointest. Surg., 1997, 1(1), 61- [82] Aki, T.; Egashira, N.; Yamauchi, Y.; Hama, M.; Yano, T.; Itoh, Y.;
67. Yamada, T.; Oishi, R. Protective effects of amino acids against
[61] Jacob, T.; Ascher, E.; Hingorani, A.; Kallakuri, S. Glycine prevents gabexate mesilate-induced cell injury in porcine aorta endothelial
the induction of apoptosis attributed to mesenteric cells. J. Pharmacol. Sci., 2008, 107(3), 238-245.
ischemia/reperfusion injury in a rat model. Surgery, 2003, 134(3), [83] Langosch, D.; Becker, C.M.; Betz, H. The inhibitory glycine
457-466. receptor: a ligand-gated chloride channel of the central nervous
[62] Kallakuri, S.; Ascher, E.; Pagala, M.; Gade, P.; Hingorani, A.; system. Eur. J. Biochem., 1990, 194(1), 1-8.
Scheinman, M.; Mehraein, K.; Jacob, T. Protective effect of [84] Danysz, W.; Parsons, C.G. Glycine and N-methyl-D-aspartate
glycine in mesenteric ischemia and reperfusion injury in a rat receptors: physiological significance and possible therapeutic
model. J. Vasc. Surg., 2003, 38(5), 1113-1120. applications. Pharmacol. Rev., 1998, 50(4), 597-664.
[63] Lee, M.A.; McCauley, R.D.; Kong, S.E.; Hall, J.C. Pretreatment [85] Pfeiffer, F.; Graham, D.; Betz, H. Purification by affinity
with glycine reduces the severity of warm intestinal ischemic- chromatography of the glycine receptor of rat spinal cord. J. Biol.
reperfusion injury in the rat. Ann. Plast. Surg., 2001, 46(3), 320- Chem., 1982, 257(16), 9389-9393.
326. [86] Jiang, L.; Qin, X.; Zhong, X.; Liu, L.; Jiang, L.; Lu, Y.; Fan, L.;
[64] Lee, M.A.; McCauley, R.D.; Kong, S.E.; Hall, J.C. Influence of He, Z.; Chen, Q. Glycine-induced cytoprotection is mediated by
glycine on intestinal ischemia-reperfusion injury. JPEN J. ERK1/2 and AKT in renal cells with ATP depletion. Eur. J. Cell
Parenter. Enteral. Nutr., 2002, 26(2), 130-135. Biol., 2011, 90(4), 333-341.
[65] Petrat, F.; Drowatzky, J.; Boengler, K.; Finckh, B.; Schmitz, K.J.; [87] Grenningloh, G.; Pribilla, I.; Prior, P.; Multhaup, G.; Beyreuther,
Schulz, R.; de Groot, H. Protection from glycine at low doses in K.; Taleb, O.; Betz, H. Cloning and expression of the 58 kd beta
ischemia-reperfusion injury of the rat small intestine. Eur. Surg. subunit of the inhibitory glycine receptor. Neuron, 1990, 4(6), 963-
Res., 2011, 46(4), 180-187. 970.
[66] Schaefer, N.; Tahara, K.; Schuchtrup, S.; Websky, M.V.; Overhaus, [88] Kuhse, J.; Laube, B.; Magalei, D.; Betz, H. Assembly of the
M.; Schmidt, J.; Wirz, S.; Abu-Elmagd, K.M.; Kalff, J.C.; Hirner, inhibitory glycine receptor: identification of amino acid sequence
A.; Türler, A. Perioperative glycine treatment attenuates motifs governing subunit stoichiometry. Neuron, 1993, 11(6),
ischemia/reperfusion injury and ameliorates smooth muscle 1049-1056.
dysfunction in intestinal transplantation. Transplantation, 2008, [89] Görne-Tschelnokow, U.; Strecker, A.; Kaduk, C.; Naumann, D.;
85(9), 1300-1310. Hucho, F. The transmembrane domains of the nicotinic
16 Mini-Reviews in Medicinal Chemistry, 2016, Vol. 16, No. 0 Pérez-Torres et al.
acetylcholine receptor contain alpha-helical and beta structures. transporters GLYT1 and GLYT2 in the rat CNS. Eur. J. Neurosci.,
EMBO J., 1994, 13(2), 338-341. 1995, 7(6), 1342-1352.
[90] Swope, S.L.; Moss, S.J.; Raymond, L.A.; Huganir, R.L. Regulation [111] Christie, G.R.; Ford, D.; Howard, A.; Clark, M.A.; Hirst, B.H.
of ligand-gated ion channels by protein phosphorylation. Adv. Glycine supply to human enterocytes mediated by high-affinity
Second Messenger Phosphoprotein Res., 1999, 33, 49-78. basolateral GLYT1. Gastroenterology, 2001, 120(2), 439-448.
[91] Stein, V.; Nicoll, R.A. GABA generates excitement. Neuron, 2003, [112] Zhang, H.X.; Lyons-Warren, A.; Thio, L.L. The glycine transport
37(3), 375-378. inhibitor sarcosine is an inhibitory glycine receptor agonist.
[92] Qu, W.; Ikejima, K.; Zhong, Z.; Waalkes, M.P.; Thurman, R.G. Neuropharmacology., 2009, 57(5-6), 551-555.
Glycine blocks the increase in intracellular free Ca2+ due to [113] Díaz-Flores, M.; Cruz, M.; Duran-Reyes, G.; Munguia-Miranda,
vasoactive mediators in hepatic parenchymal cells. Am. J. Physiol. C.; Loza-Rodríguez, H.; Pulido-Casas, E.; Torres-Ramírez, N.;
Gastrointest. Liver Physiol., 2002, 283(6), G1249-G1256. Gaja-Rodriguez, O.; Kumate, J.; Baiza-Gutman, L.A.; Hernández-
[93] Kuhse, J.; Schmieden, V.; Betz, H. Identification and functional Saavedra, D. Oral supplementation with glycine reduces oxidative
expression of a novel ligand binding subunit of the inhibitory stress in patients with metabolic syndrome, improving their systolic
glycine receptor. J. Biol. Chem., 1990, 265(36), 22317-22320. blood pressure. Can. J. Physiol. Pharmacol., 2013, 91(10), 855-
[94] Davies, P.A.; Wang, W.; Hales, T.G.; Kirkness, E.F. A novel class 860.
of ligand-gated ion channel is activated by Zn2+. G. J. Biol. Chem., [114] El Hafidi, M.; Pérez, I.; Zamora, J.; Soto, V.; Carvajal-Sandoval,
2003, 278(2), 712-717. G.; Baños, G. Glycine intake decreases plasma free fatty acids,
[95] Miller, P.S.; Beato, M.; Harvey, R.J.; Smart, T.G. Molecular adipose cell size, and BP in sucrose-fed rats. Am. J. Physiol. Regul.
determinants of glycine receptor alphabeta subunit sensitivities to Integr. Comp. Physiol., 2004, 287, R1387-R1393.
Zn2+-mediated inhibition. J. Physiol., 2005, 566(Pt 3), 657- [115] Tastesen, H.S.; Keenan, A.H.; Madsen, L.; Kristiansen, K.; Liaset,
670. B. Scallop protein with endogenous high taurine and glycine
[96] Laube, B.; Kuhse, J.; Rundström, N.; Kirsch, J.; Schmieden, V.; content prevents high-fat, high-sucrose-induced obesity and
Betz, H. Modulation by zinc ions of native rat and recombinant improves plasma lipid profile in male C57BL/6J mice. Amino
human inhibitory glycine receptors. J. Physiol., 1995, 483(Pt 3), Acids, 2014, 46(7), 1659-1671.
613-619. [116] Ham, D.J.; Murphy, K.T.; Chee, A.; Lynch, G.S.; Koopman, R.
[97] Lee, B.H.; Hwang, S.H.; Choi, S.H.; Kim, H.J.; Jung, S.W.; Kim, Glycine administration attenuates skeletal muscle wasting in a
H.S.; Lee, J.H.; Kim, H.C.; Rhim, H.; Nah, S.Y. Resveratrol mouse model of cancer cachexia. Clin. Nutr., 2014, 33(3), 448-458.
inhibits glycine receptor-mediated ion currents. Biol. Pharm. Bull., [117] Blancas-Flores, G.; Alarcón-Aguilar, F.J.; García-Macedo, R.;
2014, 37(4), 576-580. Almanza-Pérez, J.C.; Flores-Sáenz, J.L.; Román-Ramos, R.;
[98] Marvizón, J.C.; Vázquez, J.; García Calvo, M.; Mayor, F.Jr.; Ruíz Ventura-Gallegos, J.L.; Kumate, J.; Zentella-Dehesa, A.; Cruz, M.
Gómez, A.; Valdivieso, F.; Benavides J. The glycine receptor: Glycine suppresses TNF-α-induced activation of NF-κB in
pharmacological studies and mathematical modeling of the differentiated 3T3-L1 adipocytes. Eur. J. Pharmacol., 2012, 689(1-
allosteric interaction between the glycine-and strychnine-binding 3), 270-277.
sites. Mol. Pharmacol., 1986, 30(6), 590-597. [118] Almanza-Perez, J.C.; Alarcón-Aguilar, F.J.; Blancas-Flores, G.;
[99] Müller, W.E.; Snyder, S.H. Glycine high affinity uptake and Campos-Sepulveda, A.E.; Roman-Ramos, R.; Garcia-Macedo, R.;
strychnine binding associated with glycine receptors in the frog Cruz, M. Glycine regulates inflammatory markers modifying the
central nervous system. Brain Res., 1978, 143(3), 487-498. energetic balance through PPAR and UCP-2. Biomed.
[100] Dutertre, S.; Becker, C.M.; Betz, H. Inhibitory glycine receptors: Pharmacother., 2010, 64(8), 534-540.
an update. J. Biol. Chem., 2012, 287(48), 40216-40223. [119] Sugiyama, K.; Ohishi, A.; Ohnuma, Y.; Muramatsu, K.
[101] Kondratskaya, E.L.; Fisyunov, A.I.; Chatterjee, S.S.; Krishtal, O.A. Comparison between the plasma cholesterol-lowering effects of
Ginkgolide B preferentially blocks chloride channels formed by glycine and taurine in rats fed on high cholesterol diets. Agric. Biol.
heteromeric glycine receptors in hippocampal pyramidal neurons of Chem., 1989, 53(6), 1647-1652.
rat. Brain Res. Bull., 2004, 63(4), 309-314. [120] Eloranta, T.O. Tissue distribution of S-adenosylmethionine and S-
[102] Chesnoy-Marchais, D. Potentiation of glycine responses by adenosylhomocysteine in the rat. Effect of age, sex and methionine
dideoxyforskolin and tamoxifen in rat spinal neurons. Eur. J. administration on the metabolism of S-adenosylmethionine, S-
Neurosci., 2003, 17(4), 681-691. adenosylhomocysteine and polyamines. Biochem. J., 1977, 166(3),
[103] Lynch, J.W. Molecular structure and function of the glycine 521-529.
receptor chloride channel. Physiological Reviews., 2004, 84(4), [121] Iritani, N.; Nagashima, K.; Fukuda, H.; Katsurada, A.; Tanaka, T.
1051-1095. Effects of dietary proteins on lipogenic enzymes inrat liver. J.
[104] Miyakawa, N.; Uchino, S.; Yamashita, T.; Okada, H.; Nakamura, Nutr., 1986, 116(2), 190-197.
T.; Kaminogawa, S.; Miyamoto, Y.; Hisatsune, T. A glycine [122] Park, T.; Oh, J.; Lee, K. Dietary taurine or glycine supplementation
receptor antagonist, strychnine, blocked NMDA receptor activation reduces plasma and liver cholesterol and triglycerides
in the neonatal mouse neocortex. Neuroreport., 2002, 13(13), concentrations in rats fed a cholesterol-free diet. Nutrition Res.,
1667-1673. 1999, 19(12), 1777-1789.
[105] Yue, J.T.; Mighiu, P.I.; Naples, M.; Adeli, K.; Lam, T.K. Glycine [123] Jackson, A.A.; Dunn, R.L.; Marchand, M.C.; Langley-Evans, S.C.
normalizes hepatic triglyceride rich VLDL secretion by triggering Increased systolic blood pressure in rats induced by a maternal low-
the CNS in high-fat fed rats. Circ. Res., 2012, 110(10), 1345-1354. protein diet is reversed by dietary supplementation with glycine.
[106] Wilcox, K.S.; Fitzsimonds R.M.; Johnson, B.; Dichter, M.A. Clin. Sci (Lond)., 2002, 103(6), 633-639.
Glycine regulation of synaptic NMDA receptors in hippocampal [124] Newgard, C.B.; An, J.; Bain, J.R.; Muehlbauer, M.J.; Stevens,
neurons. J Neurophysiol., 1996, 76(5), 3415-3424. R.D.; Lien, L.F.; Haqq, A.M.; Shah, S.H.; Arlotto, M.; Slentz, C.;
[107] Cattani, D.; de Liz Oliveira Cavalli, V.L.; Heinz Rieg, C.E.; Rochon, J.; Gallup, D.; Ilkayeva, O.; Wenner, B.R.; Yancy, W.S.
Domingues, J.T.; Dal-Cim, T.; Tasca C.I.; Mena Barreto Silva, Jr.; Eisenson, H.; Musante, G.; Surwit, R.S.; Millington, D.S.;
F.R.; Zamoner, A. Mechanisms underlying the neurotoxicity Butler, M.D.; Svetkey, L.P. A branched-chain amino acid-related
induced by glyphosate-based herbicide in immature rat metabolic signature that differentiates obese and lean humans and
hippocampus: Involvement of glutamate excitotoxicity. contributes to insulin resistance. Cell Metab., 2009, 9(4), 311-326.
Toxicology., 2014, 320, 34-45. [125] Renner, S.; Römisch-Margl, W.; Prehn, C.; Krebs, S.; Adamski, J.;
[108] Samsel, A.; Seneff, S. Glyphosate, pathways to modern diseases Göke, B.; Blum, H.; Suhre, K.; Roscher, A.A.; Wolf, E. Changing
III: Manganese neurological diseases, and associated pathologies. . metabolic signatures of amino acids and lipids during the
Surgical Neurology International., 2015, 6:45. prediabetic period in a pig model with impaired incretin function
[109] Aragón, C.; López-Corcuera, B. Structure, function and regulation and reduced β-cell mass. Diabetes, 2012, 61(8), 2166-2175.
of glycine neurotransporters. Eur. J. Pharmacol., 2003, 479(1-3), [126] Reyes López, Y.; Pérez-Torres, I.; Zúñiga-Muñoz, A.; Guarner
249-262. Lans, V.; Díaz-Díaz, E.; Soria Castro, E.; Velázquez Espejel, R.
[110] Zafra, F.; Gomeza, J.; Olivares, L.; Aragón, C.; Giménez, C. Effect of Glycine on Adipocyte Hypertrophy in a Metabolic
Regional distribution and developmental variation of the glycine Syndrome Rat Model. Current Drug Delivery., 2015, 12, in press.
Beneficial Effects of the Amino Acid Glycine Mini-Reviews in Medicinal Chemistry, 2016, Vol. 16, No. 0 17
[127] Inyard, A.C.; Chong, D.G.; Klibanov, A.L.; Barrett, E.J. Muscle [145] Yang, J.; Liu, X.; Bhalla, K.; Kim, C.N.; Ibrado, A.M.; Cai, J.;
contraction, but not insulin, increases microvascular blood volume Peng, T.I.; Jones, D.P.; Wang, X. Revertion of apoptosis by Bcl-2:
in the presence of free fatty acid-induced insulin resistance. release of cytochrome c from mitochondria blocked. Science, 1997,
Diabetes, 2009, 58(11), 2457-2463. 275(5303), 1129-1132.
[128] Müller, W.A.; Aoki, T.T.; Cahill, G.F. Effect of alanine and [146] Zhang, Y.; Ikejima, K.; Honda, H.; Kitamura, T.; Takei, Y.; Sato,
glycine on glucagon secretion in postabsorptive and fasting obese N. Glycine prevents apoptosis of rat sinusoidal endothelial cells
man. J. Clin. Endocrinol. Metab., 1975, 40(3), 418-425. caused by deprivation of vascular endothelial growth factor.
[129] Cheng, S.; Rhee, E.P.; Larson, M.G.; Lewis, G.D.; McCabe, E.L.; Hepatology, 2000, 32(3), 542-546.
Shen, D.; Palma, M.J.; Roberts, L.D.; Dejam, A.; Souza, A.L.; [147] Brawley, L.; Torrens, C.; Anthony, F.W.; Itoh, S.; Wheeler, T.;
Deis, A.A.; Magnusson, M.; Fox, C.S.; O'Donnell, C.J.; Vasan, Jackson, A.A.; Clough, G.F.; Poston, L.; Hanson, M.A. Glycine
R.S.; Melander, O.; Clish, C.B.; Gerszten, R.E.; Wang, T.J. rectifies vascular dysfunction induced by dietary protein imbalance
Metabolite profiling identifies pathways associated with metabolic during pregnancy. J. Physiol., 2004, 554(Pt2), 497-504.
risk in humans. Circulation, 2012, 125(18), 2222-2231. [148] Jackson, A.A., The glycine story. Euro. J. Clin. Nutr., 1991, 45,
[130] Li, C.; Liu, C.; Nissim, I.; Chen, J.; Chen, P.; Dolida, N.; Zhang, 59-65.
T.; Nissim, I.; Daikhin, Y.; Stokes, D.; Yudkoff, M.; Bennett, M.J.; [149] Fukada, S.; Shimada, Y.; Morita, T.; Sugiyama K. Suppression of
Stanley, C.A.; Matschinsky, F.M.; Naji, A. Regulation of glucagon methionine-induced hyperhomocysteinemia by glycine and serine
secretion in normal and diabetic human islets by γ-hydroxybutyrate in rats. Biosci Biotechnol Biochem., 2006, 70(10), 2403-2409.
and glycine. J. Biol. Chem., 2013, 288(6), 3938-3951. [150] Mikalauskas, S.; Mikalauskiene, L.; Bruns, H.; Nickkholgh, ;
[131] Lustgarten, M.S.; Price, L.L.; Phillips, E.M.; Fielding, R.A. Serum Hoffmann, K.; Longerich, T.; Strupas, K.; Büchler, M.W.;
glycine is associated with regional body fat and insulin resistance Schemmer, P. Dietary glycine protects from chemotherapy-induced
in functionally-limited older adults. PLoS One., 2013, 8(12), hepatotoxicity. Amino Acids, 2011, 40(4), 1139-1150.
e84034. [151] Zhong, Z.; Arteel, G.E.; Connor, H.D.; Yin, M.; Frankenberg,
[132] Alarcon-Aguilar, F.J.; Almanza-Perez, J.; Blancas, G.; Angeles, S.; M.V.; Stachlewitz, R.F.; Raleigh, J.A.; Mason, R.P.; Thurman,
Garcia-Macedo, R.; Roman, R.; Cruz, M. Glycine regulates the R.G. Cyclosporin A increases hypoxia and free radical production
production of pro-inflammatory cytokines in lean and monosodium in rat kidneys: prevention by dietary glycine. Am. J. Physiol., 1998,
glutamate-obese mice. Eur. J. Pharmacol., 2008, 599(1-3), 152- 275(4 Pt 2), F595-F604.
158. [152] Soodvilai, S.; Jia, Z.; Yang, T. Hydrogen peroxide stimulates
[133] Rocha, D.M.; Faloona, G.R.; Unger, R.H. Glucagon-stimulating chloride secretion in primary inner medullary collecting duct cells
activity of 20 amino acids in dogs. J. Clin. Invest., 1972, 51(9), via mPGES-1-derived PGE2. Am. J. Physiol. Renal Physiol., 2007,
2346-2351. 293(5), F1571-F1576.
[134] Lezcano Meza, D.; Terán Ortíz, L.; Carvajal Sandoval, G.; [153] Alcaraz-Contreras, Y.;Garza-Ocañas, L.; Carcaño-Díaz, K.;
Gutiérrez de la Cadena, M.; Terán Escandón, D.; Estrada Parra, S. Ramírez-Gómez, X.S. Effect of glycine on lead mobilization, lead-
Effect of glycine on the immune response of the experimentally induced oxidative stress, and hepatic toxicity in rats. J. Toxicol.,
diabetic rats. Rev Alerg Mex., 2006, 53(6), 212-216. 2011, 2011, 430539.
[135] Alvarado-Vásquez, N.; Zamudio, P.; Cerón, E.; Vanda, B.; [154] Bilzer, M.; Baron, A.; Schauer, R.; Steib, C.; Ebensberger, S.;
Zenteno, E.; Carvajal-Sandoval, G. Effect of glycine in Gerbes, AL. Glutathione treatment protects the rat liver against
streptozotocin-induced diabetic rats. Comp. Biochem. Physiol. C. injury after warm ischemia and Kupffer cell activation. Digestion,
Toxicol. Pharmacol., 2003, 134(4), 521-527. 2002, 66(1), 49-57.
[136] Bos, D.C.; de Ranitz-Greven, W.L.; de Valk, H.W. Advanced [155] Grimble, R.F.; Jackson, A.A.; Persaud, C.; Wride, M.J.; Delers, F.;
glycation end products, measured as skin autofluorescence and Engler, R. Cysteine and glycine supplementation modulate the
diabetes complications: a systematic review. Diabetes Technol. metabolic response to tumor necrosis factor alpha in rats fed a low
Ther., 2011, 13(7), 773-779. protein diet. J. Nutr., 1992, 122(11), 2066-2073.
[137] Ramakrishnan, S.; Sulochana, K.N. Decrease in glycation of lens [156] Lubos, E.; Loscalzo, J.; Handy, D.E., Glutathione peroxidase-1 in
proteins by lysine and glycine by scavenging of glucose and health and disease: from molecular mechanisms to therapeutic
possible mitigation of cataractogenesis. Exp. Eye Res., 1993, 57(5), opportunities. Antioxid. Redox Signal., 2011, 15(7), 1957-1997.
623-628. [157] Blum, J.; Fridovich, I. Inactivation of glutathione peroxidase by
[138] Carvajal, S.G.; Medina, S.R.; Juárez, E.; Ramos, M.G.; Carvajal, superoxide radical. Arch. Biochem. Biophys., 1985, 240(2), 500-
M.E. Effect of glycine on hemoglobin glycation in diabetic 508.
patients. Proc. West. Pharmacol. Soc., 1999, 42, 31-42. [158] Wessner, B.; Strasser, E.M.; Spittler, A.; Roth E. Effect of single
[139] Alvarado-Vásquez, N.; Lascurain, R.; Cerón, E.; Vanda, B.; and combined supply of glutamine, glycine, N-acetylcysteine, and
Carvajal-Sandoval, G.; Tapia, A.; Guevara, J.; Montaño, L.F.; R,S-alpha-lipoic acid on glutathione content of myelomonocytic
Zenteno, E. Oral glycine administration attenuates diabetic cells. Clin. Nutr., 2003, 22(6), 515-522.
complications in streptozotocin-induced diabetic rats. Life Sci., [159] Garcia-Macedo, R.; Sanchez-Muñoz, F.; Almanza-Perez, J.C.;
2006, 79(3), 225-232. Duran-Reyes, G.; Alarcon-Aguilar, F.; Cruz, M. Glycine increases
[140] Bahmani, F.; Bathaie, S.Z.; Aldavood, S.J.; Ghahghaei, A. Glycine mRNA adiponectin and diminishes pro-inflammatory adipokines
therapy inhibits the progression of cataract in streptozotocin- expression in 3T3-L1 cells. Eur. J. Pharmacol., 2008, 587(1-3),
induced diabetic rats. Mol. Vis., 2012, 18, 439-448. 317-321.
[141] Muñoz-Carlin, M. de L.; Rodríguez-Moctezuma, J.R.; Gómez [160] El Hafidi, M.; Pérez, I.; Banos, G. Is glycine effective against
Latorre, J.G.; Montes-Castillo, M.L.; Juárez-Adauta, S. Effects of elevated blood pressure?. Curr. Opin. Clin. Nutr. Metab. Care,
glycine on auditory evoked potentials among diabetic patients with 2005, 9, 26-31.
auditory pathway neuropathy. Rev. Med. Chil., 2010, 138(10), [161] Nguyen, D.; Samson, S.L.; Reddy, V.T.; Gonzalez, E.V,; Sekhar,
1246-1252. R.V. Impaired mitochondrial fatty acid oxidation and insulin
[142] Sekhar, R.V.; Mckay, S.V.; Patel, S.G.; Guthikonda, A.P.; Reddy, resistance in aging: novel protective role of glutathione. Aging
V.T.; Balasubramanyam, A.; Jahoor, F. Glutathione synthesis is Cell., 2013, 12(3), 415-425.
diminished in patients with uncontrolled diabetes and restored by [162] Mauriz, J.L.; Matilla, B.; Culebras, J.M.; González, P,; González-
dietary supplementation with cysteine and glycine. Diabetes Care, Gallego, J. , Dietary glycine inhibits activation of nuclear factor
2011, 34(1), 162-167. kappa B and prevents liver injury in hemorrhagic shock in the rat.
[143] Baños, G.; Pérez-Torres, I.; El Hafidi, M. Medicinal Agents in the Free Radic. Biol. Med., 2001, 31(10), 1236-1244.
Metabolic Syndrome. Cardiovasc. & Hematol. Agents in Med. [163] Nielsen, C.B.; Flyvbjerg, A.; Bruun, J.M.; Forman, A.; Wogensen,
Chem., 2008, 6, 237-252. L.; Thomsen, K. Decreases in renal functional reserve and proximal
[144] Yin, M.; Rusyn, I.; Schoonhoven, R.; Graves, L,M.; Rusyn, E.V.; tubular fluid output in conscious oophorectomized rats:
Li, X.; Li, F.; Cox, A.D.; Harding, T.W.; Bunzendahl, H.; normalization with sex hormone substitution. J. Am. Soc. Nephrol.,
Swenberg, J.A.; Thurman, R.G. Inhibition of chronic rejection of 2003, 14(12), 3102-3110.
aortic allografts by dietary glycine. Transplantation, 2000, 69(5), [164] Heyman, S.N.; Brezis, M.; Epstein, F.H.; Spokes, K.; Rosen, S.
773-780. Effect of glycine and hypertrophy on renal outer medullary hypoxic
18 Mini-Reviews in Medicinal Chemistry, 2016, Vol. 16, No. 0 Pérez-Torres et al.
injury in ischemia reflow and contrast nephropathy. Am. J. Kidney [171] Chen, C.Y.; Wang, B.T.; Wu, Z.C.; Yu, W.T.; Lin, P.J.; Tsai,
Dis., 1992, 19(6), 578-586. W.L.; Shiesh, S.C. Glycine ameliorates liver injury and vitamin D
[165] Silva, P.; Rosen, S.; Spokes, K.; Epstein, F.H. Effect of glycine on deficiency induced by bile duct ligation. Clin. Chim. Acta., 2013,
medullary thick ascending limb injury in perfused kidneys. Kidney 420, 150-154.
Int., 1991, 39(4), 653-658. [172] Senthilkumar, R.; Nalini, N. Effect of glycine on tissue fatty acid
[166] Nagatomi, A.; Sakaida, I.; Matsumura, Y.; Okita, K. composition in an experimental model of alcohol-induced
Cytoprotection by glycine against hypoxia-induced injury in hepatotoxicity. Clin. Exp. Pharmacol. Physiol., 2004, 31(7), 456-
cultured hepatocytes. Liver, 1997, 17(2), 57-62. 461.
[167] Dong, Z.; Venkatachalam, M.A.; Weinberg, J.M.; Saikumar, P.; [173] Yin, M.; Ikejima, K.; Arteel, G.E.; Seabra, V.; Bradford, B.U.;
Patel Y. Protection of ATP-depleted cells by impermeant Kono, H.; Rusyn, I.; Thurman, R.G. Glycine accelerates recovery
strychnine derivatives: implications for glycine cytoprotection. Am. from alcohol-induced liver injury. J. Pharmacol. Exp. Ther., 1998,
J. Pathol., 2001, 158(3), 1021-1028. 286(2), 1014-1019.
[168] Dong, Z.; Patel, Y.; Saikumar, P.; Weinberg, J.M.; Venkatachalam, [174] Rose, M.L.; Madren, J.; Bunzendahl, H.; Thurman, R.G. Dietary
M.A. Development of porous defects in plasma membranes of glycine inhibits the growth of B16 melanoma tumors in mice.
adenosine triphosphate-depleted Madin-Darby canine kidney cells Carcinogenesis, 1999, 20(5), 793-798.
and its inhibition by glycine. Lab. Invest., 1998, 78(6), 657-668. [175] Rose, M.L.; Cattley, R.C.; Dunn, C.; Wong, V.; Li, X.; Thurman,
[169] Heyman, S.N.; Rosen, S.; Silva, P.; Spokes, K.; Egorin, M.J.; R.G. Dietary glycine prevents the development of liver tumors
Epstein, F.H. Protective action of glycine in cisplatin caused by the peroxisome proliferator WY-14,643. Carcinogenesis,
nephrotoxicity. Kidney Int., 1991, 40(2), 273-279. 1999, 20(11), 2075-2081.
[170] Rivera, C.A.; Bradford, B.U.; Hunt, K.J.; Adachi, Y.; Schrum, [176] McCole, D.F. The epithelial glycine transporter GLYT1: protecting
L.W.; Koop, D.R.; Burchardt, E.R.; Rippe, R.A.; Thurman, R.G. the gut from inflammation. J. Physiol., 2010, 588(Pt 7), 1033-
Attenuation of CCl(4)-induced hepatic fibrosis by GdCl(3) 1034..
treatment or dietary glycine. Am J Physiol Gastrointest Liver [177] Tariq, M.; Al Moutaery, A.R. Studies on the antisecretory, gastric
Physiol., 2001, 281(1), G200-G207. anti-ulcer and cytoprotective properties of glycine. Res. Commun.
Mol. Pathol. Pharmacol., 1997, 97(2), 185-198.