1. J Biol Chem. 1995 Mar 17;270(11):5830-8.
Protection by naringin and some other flavonoids of hepatocytic autophagy
and
endocytosis against inhibition by okadaic acid.
Gordon PB, Holen I, Seglen PO.
Department of Tissue Culture, Norwegian Radium Hospital, Montebello, Oslo.
In isolated rat hepatocytes, the protein phosphatase inhibitor okadaic
acid
exerts a strong inhibitory effect on autophagy, which can be partially
overcome
by certain protein kinase inhibitors like the isoflavone genistein. To
see if
other, more specific okadaic acid antagonists could be found among the
flavonoids, 55 different flavonoids were tested for their effect on okadaic
acid-inhibited autophagy, measured as the sequestration of electroinjected
[3H]raffinose. Naringin (naringenin 7-hesperidoside) and several other
flavanone
and flavone glycosides (prunin, neoeriocitrin, neohesperidin, apiin, rhoifolin,
kaempferol 3-rutinoside) offered virtually complete protection against
the
autophagy-inhibitory effect of okadaic acid. Unlike genistein, these compounds
had little or no autophagy-inhibitory effect of their own. Their innocuousness
appeared to be related to glycosylation, because the corresponding aglycones
(naringenin, eriodictyol, hesperetin, apigenin, kaempferol) were all inhibitory,
in particular apigenin (80% inhibition at 100 microM). Naringin, the most
potent
okadaic acid-antagonistic flavonoid, gave half-maximal protection at 5
microM
and maximal effect at 100 microM. Naringin also prevented the okadaic
acid-induced inhibition of endogenous, autophagic lysosomal protein degradation
and of receptor-mediated asialoglycoprotein uptake and degradation. Naringin
and
other okadaic acid-antagonistic flavonoids may be useful tools in the
study of
intracellular protein phosphorylation and could have potential therapeutic
value
as protectants against pathological hyperphosphorylations, environmental
toxins,
or side effects of chemotherapeutic drugs.
Alcohol – effects on **
2. Life Sci. 2003 Jul 4;73(7):933-46.
Role of naringin supplement in regulation of lipid and ethanol metabolism
in
rats.
Seo HJ, Jeong KS, Lee MK, Park YB, Jung UJ, Kim HJ, Choi MS.
Department of Food Science and Nutrition, Kyungpook National University,
1370
Sankyuk Dong Puk-ku, Daegu 702-701, South Korea.
The current study was performed to investigate the effect of naringin
supplements on the alcohol, lipid, and antioxidant metabolism in ethanol-treated
rats. Male Sprague-Dawley rats were randomly divided into six groups (n
= 10)
based on six dietary categories: ethanol and naringin-free, ethanol (50
g/L)
plus low-naringin (0.05 g/L), ethanol plus high-naringin (0.125 g/L),
and three
corresponding pair-fed groups. The pair-fed control rats received an isocaloric
diet containing dextrin-maltose instead of ethanol for 5 wks. Among the
ethanol
treated groups, the naringin supplements significantly lowered the plasma
ethanol concentration with a simultaneous increase in the ADH and/or ALDH
activities. However, among the ethanol-treated groups, naringin supplementation
resulted in a significant decrease in the hepatic triglycerides and plasma
and
hepatic total cholesterol compared to that in the naringin-free group.
Naringin
supplementation significantly increased the HDL-cholesterol and HDL-C/total-C
ratio, while lowering the AI value among the ethanol-treated groups. Hepatic
lipid accumulation was also significantly reduced in the naringin-supplemented
groups compared to the naringin-free group among the ethanol-treated groups,
while no differences were found among the pair-fed groups. Among the
ethanol-treated groups, the low-naringin supplementation resulted in a
significant decrease in the levels of plasma and hepatic TBARS, whereas
it
resulted in higher SOD and GSH-Px activities and gluthathion levels in
the
liver. Accordingly, naringin would appear to contribute to alleviating
the
adverse effect of ethanol ingestion by enhancing the ethanol and lipid
metabolism as well as the hepatic antioxidant defense system.
Anti-Inflammatory **
3. J Lipid Res. 2003 Feb;44(2):380-7. Epub 2002 Nov 04.
Modulation by flavonoids of PAF and related phospholipids in endothelial
cells
during oxidative stress.
Balestrieri ML, Castaldo D, Balestrieri C, Quagliuolo L, Giovane A, Servillo
L.
Department of Biochemistry and Biophysics, Second University of Naples,
Italy.
PAF-dependent transacetylase (TA) modifies the functions of platelet-activating
factor (PAF), a potent inflammatory lipid, either by transferring the
acetyl
group from PAF to lysophospholipids (TAL activity), or to sphingosine
(TAS
activity) or by hydrolyzing PAF (acetylhydrolase activity). In stimulated
endothelial cells (EC), TAL activity contributes to the synthesis of acyl-PAF,
an acyl analog of PAF, that antagonizes PAF functions and is regulated
by the
cellular redox state. In this study, we investigated the possible involvement
of
TA in the flavonoid antioxidant mechanism(s) during oxidative stress in
EC
induced by hydrogen peroxide. The treatment of EC with H2O2 resulted in
4-fold
increase of the acetyl-CoA acetyltransferase activity (AT), that is responsible
for PAF biosynthesis, while the TAL activity increased only by 53%. However,
the
preincubation of H2O2-treated EC with the flavonoids hesperedin, naringin,
and
quercetin strongly inhibited AT activity and activated TAL by 290%, 340%,
and
250%, respectively. The induction of TAL activity resulted in enhanced
biosynthesis of 1-acyl-2-[3H]acetyl-PAF in intact EC and was related to
the
flavonoid structure. These findings suggest that TAL is involved in the
Anti-Inflammatory **
Cancer **
4. Biochem Pharmacol. 2003 Oct 1;66(7):1139-50.
Rutinoside at C7 attenuates the apoptosis-inducing activity of flavonoids.
Chen YC, Shen SC, Lin HY.
Graduate Institute of Pharmacognosy, Taipei Medical University, 250 Wu-Hsing
Street, ROC, Taipei, Taiwan
Rutinoside (rhamnoglucoside; rhamnose+glucose) addition has been examined
extensively in the metabolism of flavonoids, however the effect of rutinoside
on
apoptosis-inducing activity of flavonoids is still unknown. In the present
study, the two pairs of flavonoids of hesperetin (HT) and hesperidin (HD;
HT-7-rutinose), and naringenin (NE) and naringin (NE-7-rutinose), were
used to
study their apoptosis-inducing activities in HL-60 cells. Both HD and
NI are
flavonoids which contain a rutinoside at the C7 of HT and NE, respectively.
Results of the MTT assay showed that HT and NE, but not HD and NI, exhibited
significant cytotoxic effect in HL-60 cells, accompanied by the dose-
and
time-dependent appearance of characteristics of apoptosis including an
increase
in DNA ladder intensity, morphological changes, appearance of apoptotic
bodies,
and an increase in hypodiploid cells by flow cytometry analysis. HT and
NE, but
not HD and NI, caused rapid and transient induction of caspase-3/CPP32
activity,
but not caspase-1 activity, according to the cleavage of caspase-3 substrates
poly(ADP-ribose) polymerase and D4-GDI proteins, the appearance of cleaved
caspase-3 fragments detected in HT- or NE-, but not in HD- or NI-treated
HL-60
cells. A decrease in the anti-apoptotic protein, Mcl-1, was detected in
HT- and
NE-treated HL-60 cells, whereas other Bcl-2 family proteins including
Bax,
Bcl-2, Bcl-XL, and Bag remained unchanged. The caspase-3 inhibitor, Ac-DEVD-FMK,
but not the caspase-1 inhibitor, Ac-YVAD-FMK, attenuated HT- and NE-induced
cell
death. Interestingly, neither HT nor NE induced apoptosis in the mature
monocytic cell line THP-1 and primary human polymorphonuclear cells, as
characterized by a lack of DNA ladders, caspase-3 activation, poly(ADP-ribose)
polymerase cleavage, and Mcl-1 decrease, compared with those in HL-60
cells. In
addition, the rutinoside group in HD and NI was removed by hesperidinase
and
naringinase, accompanied by the production of HT and NE, respectively,
according
to HPLC analysis. Accordingly, hesperidinase and naringinase digestion
recovered
the apoptosis-inducing activity of HD and NI in HL-60 cells. Our experiments
provide the first evidence to suggest that rutinoside in flavonoids prevents
the
induction of apoptosis, and that activation of the traditional caspase-3
cascade
participates in HT- and NE-induced apoptosis.
5. J Pharmacol Sci. 2003 Jun;92(2):166-70.
Effects of naringin on hydrogen peroxide-induced cytotoxicity and apoptosis
in
p388 cells.
Kanno S, Shouji A, Asou K, Ishikawa M.
Department of Pharmacology and Toxicology, Cancer Research Institute,
Tohoku
Pharmaceutical University. syu-kan@tohoku-pharm.ac.jp
Flavonoids are widely recognized as naturally occurring antioxidants.
Naringin
(NG) is one of the flavonoid components in citrus fruits such as grapefruit.
Hydrogen peroxide (H2O2) causes cytotoxicity through oxidative stress
and
apoptosis. In this paper, we examined the effects of NG on H2O2-induced
cytotoxicity and apoptosis in mouse leukemia P388 cells. Cytotoxicity
was
determined by mitochondrial activity (MTT assay). Apoptosis and DNA damage
were
analyzed by measuring chromatin condensation and Comet assay (alkaline
single
cell gel electrophoresis), respectively. H2O2-induced cytotoxicity was
significantly attenuated by NG or the reduced form of glutathione (GSH),
a
typical intracellular antioxidant. NG suppressed chromatin condensation
and DNA
damage induced by H2O2. These results indicate that NG from natural products
is
a useful drug having antioxidant and anti-apoptopic properties.
6. Anticancer Res. 2000 Sep-Oct;20(5A):3323-9.
Effects of citrus phytochemicals on liver and lung cytochrome P450 activity
and
on the in vitro metabolism of the tobacco-specific nitrosamine NNK.
Bear WL, Teel RW.
Department of Physlology and Pharmacology, Loma Linda University, School
of
Medicine, CA 92350, USA.
NNK is a potent environmental carcinogen to which both smokers and nonsmokers
are exposed. The response to NNK may be affected by factors including
nutrition.
We investigated the effects of five citrus phytochemicals on the in vitro
metabolism of the tobacco-specific nitrosamine NNK and on the dealkylation
of
methoxyresorufin (MROD) and pentoxyresorufin (PROD) in liver and lung
microsomes
of the Syrian golden hamster. In the NNK metabolism experiments in vitro
incubations contained 3 microCi [5-H3] NNK, 0.5 mg microsomal protein
and 0.5
mumole of the citrus phytochemical diosmin, naringin, naringenin, quercetin
or
rutin. In the dealkylation studies incubations contained 0.5 microM
methoxyresorufin or pentoxyresorufin, 0.5 mg microsomal protein and 0.5
mumole
of citrus phytochemical. The major NNK metabolism pathway in hamster liver
microsomes was NNK-reduction while in lung microsomes it was
alpha-hydroxylation. The alpha-hydroxylation pathway produces metabolic
products
that methylate and pyridyloxobutylate DNA. Naringenin, a metabolite of
naringin,
and quercetin were the most potent inhibitors of alpha-hydroxylation of
NNK in
both liver and lung microsomes. This inhibition correlated with a potent
inhibition of MROD and PROD activity in liver but not in lung microsomes.
The
metabolic activation of NNK is associated with cytochrome P450 isoforms
1A1,
1A2, 2B1, 2D6 and 2E1. Our results suggest that naringenin and quercetin
from
citrus fruits inhibit the activity of cytochrome P450 (CYP) isoforms that
activate NNK and may afford protection against NNK-induced carcinogenesis.
Antioxidant properties / ROS **
7. Pharmazie. 2003 Aug;58(8):564-6.
Naringin and naringenin inhibit nitrite-induced methemoglobin formation.
Kumar MS, Unnikrishnan MK, Patra S, Murthy K, Srinivasan KK.
Department of Pharmacology, College of Pharmaceutical Sciences, Manipal,
India.
Naringin and naringenin protect hemoglobin from nitrite-induced oxidation
to
methemoglobin. The protection is not observed when naringin and naringenin
are
added after the autocatalytic stage of the oxidation of hemoglobin by
nitrite.
The ability of naringin and naringenin to scavenge oxygen free radicals
may be
responsible for the action because superoxide, hydroxyl and other free
radicals
are implicated in promoting the autocatalytic stage of oxidation of hemoglobin
by nitrite. Both compounds showed less ability to protect intact erythrocytes
suggesting that they may not cross the erythrocyte membrane in sufficient
amounts. Naringenin was more effective than naringin, probably because
of the
extra phenolic group in the aglycone.
8. Prostaglandins Leukot Essent Fatty Acids. 2003 Jul;69(1):73-7.
Effects of flavonoids on the susceptibility of low-density lipoprotein
to
oxidative modification.
Safari MR, Sheikh N.
Department of Biochemistry and Nutrition, School of Medicine, Hamadan
University
of Medical Sciences and Health Services, Hamadan, Iran. safari@umsha.ac.ir
Dietary flavonoid intake has been reported to be inversely associated
with the
incidence of coronary artery disease. To clarify the possible role of
flavonoids
in the prevention of atherosclerosis, we investigated the effects of some
of
these compounds on the susceptibility of low-density lipoprotein (LDL)
to
oxidative modification. In this study, six flavonoids, "apigenin,
genistein,
morin, naringin, pelargonidin and quercetin", were added to plasma
and incubated
for 3h at 37 degrees C. Then, the LDL fraction was separated by
ultracentrifugation. The oxidizability of LDL was estimated by measuring
conjugated diene (CD), lipid peroxides and thiobarbituric acid-reactive
substances (TBARS) after cupric sulfate solution was added. We showed
that among
flavonoids used, quercetin and morin significantly (P<0.01 by ANOVA)
and
dose-dependently prolonged the lag time before initiation of oxidation
reaction.
Also, these two flavonoids suppressed the formation of lipid peroxides
and TBARS
more markedly than others. Their ability to prolong lag time and suppression
of
lipid peroxides and TBARS formation resulted to be in the following order:
quercetin>morin>pelargonidin>genistein>naringin>apigenin.
LDL exposed to
flavonoids in vitro reduced oxidizability. These findings show that flavonoids
may have a role in ameliorating atherosclerosis.
9. Mol Cell Biochem. 2003 Apr;246(1-2):193-6.
Anti-oxidant effect of flavonoids on the susceptibility of LDL oxidation.
Naderi GA, Asgary S, Sarraf-Zadegan N, Shirvany H.
Department of Biochemistry, Isfahan Cardiovascular Research Center, Amin
Hospital, Isfahan University of Medical Sciences, Isfahan, Iran.
isfcarvasrc@hotmail.com
In vitro studies have demonstrated increased atherogenicity of oxidized
low-density lipoprotein (ox-LDL) compared to native LDL. Oxidative modification
of LDL alters its structure allowing LDL to be taken up by scavenger receptors
on macrophage, endothelial, and smooth muscle cells, leading to the formation
of
lipid-laden foam cells, the hallmark of early atherosclerotic lesions.
The
susceptibility of LDL to in vitro oxidation was assessed essentially by
the
technique described by Esterbauer et al. LDL oxidation were monitored
by change
in 234-absorbance in the presence and absence of pure flavonoids. Morin,
genistein, apigenin and biochanin A, naringin and quercetin were used
at
different concentration. These flavonoids significantly inhibit in vitro
LDL
oxidation, genistein, morin and naringin have stronger inhibitory activity
against LDL oxidation than biochanin A or apigenin. This study show that
flavonoids prevent in vitro LDL oxidation and probably would be important
to
prevent atherosclerosis.
HEMATOCRITS – NORMALIZATION **
10. Int J Vitam Nutr Res. 1988;58(4):414-7.
Ingestion of grapefruit lowers elevated hematocrits in human subjects.
Robbins RC, Martin FG, Roe JM.
Food Science and Human Nutrition Department, IFAS, University of Florida,
Gainesville.
This study was based on in vitro observations that naringin isolated
from
grapefruit induced red cell aggregation and evidence that clumped red
cells are
removed from the circulation by phagocytosis. The effect on hematocrits
of
adding grapefruit to the daily diet was determined using 36 human subjects
(12
F, 24 M) over a 42-day study. The hematocrits ranged from 36.5 to 55.8%
at the
start and 38.8% to 49.2% at the end of the study. There was a differential
effect on the hematocrit. The largest decreases occurred at the highest
hematocrits and the effect decreased on the intermediate hematocrits;
however,
the low hematocrits increased. There was no significant difference between
ingesting 1/2 or 1 grapefruit per day but a decrease in hematocrit due
to
ingestion of grapefruit was statistically significant at the p less than
0.01
level.
ANIMAL **
11. Drug Metabol Drug Interact. 2000;17(1-4):351-63.
Effect of the grapefruit flavonoid naringin on pharmacokinetics of quinine
in
rats.
Zhang H, Wong CW, Coville PF, Wanwimolruk S.
Natural & Complementary Medicine Research, New Zealand 's National
School of
Pharmacy, University of Otago, Dunedin. hu.zhang@stonebow.otago.ac.nz
The effect of the grapefruit flavonoid naringin, an inhibitor of CYP3A4,
on the
pharmacokinetics of quinine in rats after oral or intravenous (i.v.) dosing
of
quinine was investigated. Female Wistar rats (wt 190-220 g) were used
in two
separate studies, i.e. oral and i.v. administration of quinine. The animals
were
divided into two groups, one served as control and the other group was
pretreated with 25 mg/kg naringin once a day for 7 consecutive days before
the
pharmacokinetic study. On the study day, quinine (25 mg/kg) was administered
to
the rats by either the oral or i.v. route. Blood samples were collected
at
different times, up to 6 h after quinine administration. Plasma quinine
concentration was assayed by HPLC. Pretreatment with naringin did not
cause any
significant change in the pharmacokinetics of quinine after the i.v. dose.
However pretreatment with naringin led to a 208% increase in peak plasma
concentration (Cmax), a 93% increase in time to reach Cmax (tmax), and
a 152%
increase in the area under the plasma concentration-time curve (AUC) of
quinine
after oral administration. Consequently, the oral bioavailability of quinine
was
significantly increased (p < 0.05) from 17% (control) to 42% after
pretreatment
with naringin. There was no significant difference in the elimination
half-life
(t(1/2)beta) of quinine between the two groups. These results suggest
that
pretreatment with the grapefruit flavonoid naringin is associated with
increased
oral bioavailability of quinine in rats.
ALCOHOL Induced ULCER and ULCERS **
12. Pharmacology. 1994 Sep;49(3):144-50.
Antiulcer effect of naringin on gastric lesions induced by ethanol in
rats.
Martin MJ, Marhuenda E, Perez-Guerrero C, Franco JM.
Departamento de Farmacia y Tecnologia Farmaceutica, Facultad de Farmacia,
Universidad de Sevilla, Espana.
This study was designed to determine the gastroprotective properties
of naringin
on and the involvement of endogenous prostaglandins in mucosal injury
produced
by absolute ethanol. Oral pretreatment with the highest dose of naringin
(400
mg/kg), 60 min before absolute ethanol was the most effective antiulcer
treatment. Subcutaneous administration of indomethacin (10 mg/kg) to the
animals
treated with naringin (400 mg/kg) partially inhibited gastric protection,
but
the prostaglandin E2 determination did not show any increase in prostanoid
levels. The contents of gastric mucus and total proteins were not significantly
modified. Naringin-treated rats showed a marked increase in hexosamine
levels,
but this increase was less in animals pretreated with indomethacin. These
results show that naringin has a 'cytoprotective' effect against ethanol
injury
in the rat, but this property appears to be mediated by non-prostaglandin-dependent
mechanisms.
13. Int J Tissue React. 1983;5(4):415-20.
The gastric anti-ulcer activity of naringenin, a specific histidine
decarboxylase inhibitor.
Parmar NS.
The gastric anti-ulcer activity of a specific histidine decarboxylase
inhibitor
naringenin, the aglycone of naringin, a naturally occurring flavanone
glycoside
obtained from kino and grapefruits, has been studied on the various types
of
ulcers experimentally induced in rats, viz., pylorus-ligated (Shay method)
and
restraint ulcers, and on the gastric mucosal damage induced by aspirin,
phenylbutazone or reserpine. Naringenin possessed significant anti-ulcer
activity in all these models, manifesting a dose-dependent anti-ulcer
effect on
the pylorus-ligated and restraint ulcers. However, the ED50 value against
ulcers
in the pylorus-ligated rats (132 mg/kg) was significantly greater than
that
against ulcers in the restraint rats (42 mg/kg). Amongst all the models
used,
naringenin was found most effective against the restraint rats. It is
suggested
that a mechanism involving the inhibition of formation and release of
endogenous
histamine in the gastric mucosa of rats is implicated in the protective
effect
of naringenin.
ANTI-OXIDANT – ROS
14: Clin Chim Acta. 2002 Mar;317(1-2):181-90.
Comparison of antioxidant effects of naringin and probucol in cholesterol-fed
rabbits.
Jeon SM, Bok SH, Jang MK, Kim YH, Nam KT, Jeong TS, Park YB, Choi MS.
Department of Food Science and Nutrition, Kyungpook National University,
1370
Sankyuk Dong Puk-ku, 702-701, Taegu, South Korea.
BACKGROUND: Due to the strong evidence on the involvement of active oxygen
species in a variety of disorders, the role of antioxidants against oxidative
stress has recently received increased attention. METHODS: Twenty male
rabbits
were served a high-cholesterol (HC, 5 g/kg diet) diet or high-cholesterol
diet
supplemented with naringin (0.5 g/kg diet) or probucol (0.5 g/kg diet)
for 8
weeks to compare the antioxidative effects of the citrus bioflavonoid
(naringin)
and antioxidative cholesterol-lowering drug (probucol). RESULTS: The plasma
thiobarbituric acid-reactive substances (TBARS) concentration was not
significantly different between the groups, whereas the hepatic TBARS
concentration was significantly lower in the probucol group than in both
normal
and HC control or naringin group. Probucol and naringin supplementation
led to
an increase in the hepatic superoxide dismutase (SOD) and catalase (CAT)
activities, and a decrease in the hepatic mitochondrial hydrogen peroxide
(H(2)O(2)) content compared to the HC-control group. However, there was
no
difference in the cytosolic H(2)O(2) content or cytosolic glutathion peroxidase
(GSH-Px) activity in the liver between the groups. Both naringin and probucol
supplements significantly increased the plasma vitamin E concentration
compared
to the HC-control group. As regards the antioxidant enzyme gene expressions,
naringin significantly increased the expression of three antioxidant enzyme
mRNAs compared to the HC-control group, whereas probucol significantly
increased
the only SOD mRNA expression. CONCLUSIONS: The probucol supplement was
very
potent in the antioxidative defense system, whereas naringin exhibited
a
comparable antioxidant capacity based on increasing the gene expressions
in the
antioxidant enzymes, while also increasing the hepatic SOD and CAT activities,
sparing plasma vitamin E, and decreasing the hepatic mitochondrial H(2)O(2)
content.
ANTI-VIRAL **
15. Biol Pharm Bull. 2003 Jan;26(1):108-9.
Anti-Sindbis activity of flavanones hesperetin and naringenin.
Paredes A, Alzuru M, Mendez J, Rodriguez-Ortega M.
Biomedical Institute, Venezuelan Central University, PO BOX 4043, Caracas
1010A,
Venezuela.
The effect of hesperetin, naringenin and its glycoside form on the Sindbis
neurovirulent strain (NSV) replication in vitro was studied. All flavanones
tested were not cytotoxic on Baby Hamster cells 21 clone 15 (BHK-21).
Antiviral
effect was evaluated by a colorimetric assay using MTT (3-(4,5
dimethylthiazol-2-yl)-2,5-dipheyl-tetrazolium bromide) and by plaque reduction
assay. Hesperetin and naringenin had inhibitory activity on NSV infection.
The
50% inhibitory doses (ID(50%)) of both compounds were 20.5 and 14.9 microg/ml
respectively, as established by plaque assay. However their glycosides,
hesperidin and naringin did not have inhibitory activity. Implying that
the
presence of rutinose moiety of flavanones blocks the antiviral effect.
Oxygenation on the 3' positions at the B rings on the hesperetin skeleton
decrease the anti viral activity at 25 microg/ml.
CANCER **
16. Mutagenesis. 2003 Jul;18(4):337-43.
Naringin, a citrus flavonone, protects against radiation-induced chromosome
damage in mouse bone marrow.
Jagetia GC, Venkatesha VA, Reddy TK.
Department of Radiobiology, Kasturba Medical College, Manipal 576119,
India.
gc.jagetia@kmc.manipal.edu
Free radicals are responsible for the induction of damage to the cellular
DNA
that leads to the formation of chromosome aberrations. Antioxidants are
known to
scavenge free radicals, thereby decreasing the degree of such effects.
Radiation
is a well-known inducer of free radicals and compounds that can scavenge
free
radicals may reduce radiation-induced DNA damage. Naringin, a bioflavonoid
predominant in grapefruit and other citrus fruits, has been found to scavenge
free radicals, therefore it may also reduce radiation-induced damage.
The aim of
the present study was to evaluate the radioprotective action of 2 mg/kg
naringin
in the bone marrow of mice exposed to different doses of (60)Co gamma-radiation
by scoring the frequency of asymmetrical chromosomal aberrations. The
irradiation of mice resulted in a dose-dependent elevation in the frequency
of
aberrant cells, acentric fragments, chromatid and chromosome breaks, dicentrics
and exchanges. All these aberrations were elevated with scoring time up
to 24 h
post-irradiation and declined thereafter, except chromatid breaks, which
were
maximum at 12 h post-irradiation. Treatment of mice with 2 mg/kg body
wt
naringin before exposure to various doses of gamma-radiation resulted
in a
significant reduction in the frequencies of aberrant cells and chromosomal
aberrations like acentric fragments, chromatid and chromosome breaks,
centric
rings, dicentrics and exchanges. The evaluation of free radical scavenging
activity of naringin revealed a dose-dependent scavenging of hydroxyl,
superoxide and 2,2 equal to or precedes -diphenyl-1-picryl hydrazyl radical.
Naringin at 5 microM scavenged the 2,2-azino-bis-3-ethyl
benzothiazoline-6-sulphonic acid cation radical very efficiently, where
a 90%
scavenging was observed. Our study demonstrates that naringin can protect
mouse
bone marrow cells against radiation-induced chromosomal damage.
17. Mutat Res. 2002 Aug 26;519(1-2):37-48.
The grapefruit flavanone naringin protects against the radiation-induced
genomic
instability in the mice bone marrow: a micronucleus study.
Jagetia GC, Reddy TK.
Department of Radiobiology, Kasturba Medical College, Manipal 576119,
India.
gc.jagetia@kmc.manipal.edu
The effect of various doses, viz. 0, 0.5, 1, 2, 4, 6 and 8 mg/kg body
weight of
naringin (NIN) (a citrus flavanone) was studied on the alteration in the
radiation-induced micronucleated polychromatic (MPCE) and normochromatic
(MNCE)
erythrocytes in mouse bone marrow exposed to 2 Gy of 60Co gamma-radiation.
The
treatment of mice with various doses of NIN before exposure to 2 Gy resulted
in
a significant decline in the frequency of MPCE when compared to the
non-drug-treated irradiated control. However, the greatest reduction in
MPCE was
observed for 2mg/kg body weight NIN, accompanied by a highest PCE/NCE
ratio when
compared with the non-drug-treated irradiated control. Therefore, further
studies were carried out using this dose of NIN, where the animals were
administered with 2mg/kg body weight of NIN before exposure to 0, 0.5,
1, 2, 3
and 4 Gy of gamma-radiation. The frequency of MPCE and MNCE increased
in a
dose-dependent manner in both the non-drug-treated irradiated control
and
NIN-pretreated irradiated groups up to a dose of 2 Gy, while a further
increase
in the irradiation dose resulted in a significant decline in MPCE and
MNCE
frequencies in both groups. Pretreatment of mice with 2mg/kg body weight
of NIN
resulted in a significant decline in the frequencies of MPCE and MNCE.
NIN
treatment not only reduced the frequency of MPCE with one micronucleus,
but also
of MPCE with multiple micronuclei (MN), indicating its ability to reduce
complex
chromosome aberrations. Conversely, the PCE/NCE ratio declined in a
dose-dependent manner in both groups. The treatment of mice with NIN before
exposure to different doses of gamma-radiation resulted in the inhibition
in
this decline in the PCE/NCE ratio. Our study demonstrates that NIN is
able to
protect mouse bone marrow cells against the radiation-induced DNA damage
and
decline in the cell proliferation as observed by a reduction in the micronucleus
frequency and an increase in PCE/NCE ratio, respectively, in the NIN-pretreated
irradiated group.
18. Life Sci. 1999;65(24):2591-602.
In vitro and in vivo effects of naringin on cytochrome P450-dependent
monooxygenase in mouse liver.
Ueng YF, Chang YL, Oda Y, Park SS, Liao JF, Lin MF, Chen CF.
National Research Institute of Chinese Medicine, Taipei, Taiwan, ROC.
ueng@cma23.nricm.edu.tw
In vitro and in vivo effects of naringin on microsomal monooxygenase
were
studied to evaluate the drug interaction of this flavonoid. In vitro addition
of
naringin up to 500 microM had no effects on benzo(a)pyrene hydroxylase
(AHH)
activity of mouse liver microsomes. In contrast, the aglycone naringenin
at 300
to 500 microM decreased AHH activity by 50% to 60%. Analysis of Lineweaver-Burk
and Dixon plots indicated that naringenin competitively inhibited AHH
activity
with an estimated Ki of 39 microM. Naringenin at 100 microM also reduced
metabolic activation of benzo(a)pyrene to genotoxic products as monitored
by
umuC gene expression response in Salmonella typhimurium TA1535/pSK1002.
In the
presence of equimolar naringenin and benzo(a)pyrene, umuC gene expression
presented as beta-galactosidase activity was reduced to a level similar
to the
control value. Administration of a liquid diet containing 10 mg/ml naringin
for
7 days caused 38% and 49% decreases of AHH and 7-methoxyresorufin O-demethylase
activities, respectively. In contrast, the administration had no effects
on
cytochrome P450 (P450)-catalyzed oxidations of 7-ethoxyresorufin,
7-ethoxycoumarin, N-nitrosodimethylamine, nifedipine, erythromycin and
testosterone. Microsomal P450 and cytochrome b5 contents and NADPH-P450
reductase activity were not affected. Immunoblot analysis using MAb 1-7-1,
which
immunoreacted with both P450 1A1 and 1A2, revealed that the level of P450
1A2
protein was decreased by 38%. These results demonstrate that naringenin
is a
potent inhibitor of AHH activity in vitro and naringin reduces the P450
1A2
protein level in vivo. These effects may indicate a chemopreventive role
of
naringin against protoxicants activated by P450 1A2.
19. Eur J Pharmacol. 1999 Mar 5;368(2-3):245-50.
Suppression of lipopolysaccharide-induced tumor necrosis factor-release
and
liver injury in mice by naringin.
Kawaguchi K, Kikuchi S, Hasegawa H, Maruyama H, Morita H, Kumazawa Y.
Medicinal Plant Garden, School of Pharmaceutical Sciences, Kitasato University,
Sagamihara, Japan.
Suppressive effects of naringin on lipopolysaccharide-induced tumor necrosis
factor (TNF) release followed by liver injury were investigated. Intraperitoneal
(i.p.) treatment with naringin prior to an intravenous (i.v.) challenge
of
lipopolysaccharide significantly reduced serum TNF levels in a dose-dependent
manner and was the most effective when administered 60 min prior to
lipopolysaccharide challenge. Treatment with naringin 3 h prior to
lipopolysaccharide challenge resulted in complete protection from
lipopolysaccharide lethality in D-galactosamine-sensitized mice. Histological
estimation revealed that massive cell infiltration followed by severe
injury
developed in the livers of lipopolysaccharide-treated and
D-galactosamine-treated mice unless they had been pretreated with naringin.
Appearance of apoptotic cells was also found to decrease by treatment
with
naringin. Increases in serum levels of aspartate aminotransferase, alanine
aminotransferase and creatine kinase, responsible for lipopolysaccharide-induced
liver injury, blocked by naringin administration and the levels were nearly
to
the normal level. These results indicate that action of naringin is mediated
through suppression of lipopolysaccharide-induced TNF production.
20. Carcinogenesis. 1989 Oct;10(10):1953-5.
Modulating effect of plant flavonoids on the mutagenicity of
N-methyl-N'-nitro-N-nitrosoguanidine.
Francis AR, Shetty TK, Bhattacharya RK.
Biochemistry Division, Bhabha Atomic Research Centre, Bombay India.
Tests have been carried out with several plant flavonoids to detect their
ability to suppress mutagenesis in Salmonella typhimurium strain TA100
NR
induced by the direct-acting carcinogen N-methyl-N'-nitro-N-nitrosoguanidine.
Among the most effective flavonoids are the isoflavone, biochanin A, the
flavanone glycoside, naringin, and its aglycone, naringenin, and several
flavonols, e.g. morin, fisetin, kaempferol, gossypetin and quercetin,
including
a flavonol glycoside, rutin. In particular, naringin possesses exceptional
antimutagenic activity, in as much as, less than half the equimolar amount
can
reduce the mutagenic potency of this carcinogen by 50%. These flavonoids
appear
to act either by preventing passage of the carcinogen into bacterial cells
or by
altering some cellular processes.
CHOLESTEROL **
21. Arch Latinoam Nutr. 2001 Sep;51(3):258-64.
[Hypocholesterolemic effect of naringin and rutin flavonoids]
[Article in Portuguese]
da Silva RR, de Oliveira TT, Nagem TJ, Pinto AS, Albino LF, de Almeida
MR, de
Moraes GH, Pinto JG.
Universidade Federal de Vicosa, Minas Gerais, Brazil.
Flavonoids are pigments fenolics of plants that possess several biological
activities, and many of these are associated with prevention of chronic
diseases
as cancer and hyperlipidemia. This work had as objective evaluates the
effect of
the flavonoids naringin and rutin on the metabolism lipidic of chicks
hypercholesterolemic. In agreement with the results it can be observed
that
naringin and rutin reduced the levels of total cholesterol significantly,
cholesterol-LDL, cholesterol-VLDL and triglycerols, not presenting, however,
reductions in the levels of cholesterol-HDL.
22. Life Sci. 2001 Nov 2;69(24):2855-66.
Antioxidative activity of naringin and lovastatin in high cholesterol-fed
rabbits.
Jeon SM, Bok SH, Jang MK, Lee MK, Nam KT, Park YB, Rhee SJ, Choi MS.
Korea Institute of Bioscience and Biotechnology, KIST, Yusong, Taejon.
The consumption of a cholesterol-enriched diet increases the degree of
lipid
peroxidation, which is one of the early processes of atherosclerosis.
The aim of
this trial was to determine the antioxidative effects of the citrus
bioflavonoid, naringin, a potent cholesterol-lowering agent, compared
to the
cholesterol-lowering drug, lovastatin, in rabbits fed a high cholesterol
diet.
Male rabbits were served a high-cholesterol (0.5%, w/w) diet or high-cholesterol
diet supplemented with either naringin (0.5% cholesterol, 0.05% naringin,
w/w)
or lovastatin (0.5% cholesterol, 0.03% lovastatin, w/w) for 8 weeks to
determine
the plasma and hepatic lipid peroxide, plasma vitamin A and E levels,
and
hepatic hydrogen peroxide levels, along with the hepatic antioxidant enzyme
activities and gene expressions. Only the lovastatin group showed significantly
lower plasma and hepatic lipid peroxide levels compared to the control
group.
The naringin supplementation significantly increased the activities of
both
hepatic SOD and catalase by 33% and 20%, respectively, whereas the lovastatin
supplementation only increased the catalase activity by 23% compared to
control
group. There was no difference in the GSH-Px activities between the various
groups. Content of H2O2 in hepatic mitochondria was significantly lower
in
groups supplemented with lovastatin and naringin than in control group.
However,
there was no difference in cytosolic H2O2 content in liver between groups.
The
concentration of plasma vitamin E was significantly increased by the naringin
supplementation. When comparing the antioxidant enzyme gene expression,
the mRNA
expression of SOD, catalase and GSH-Px was significantly up-regulated
in the
naringin-supplemented group. Accordingly, these results would appear to
indicate
that naringin, a citrus bioflavonoid, plays an important role in regulating
antioxidative capacities by increasing the SOD and catalase activities,
up-regulating the gene expressions of SOD, catalase, and GSH-Px, and protecting
the plasma vitamin E. In contrast, lovastatin exhibited an inhibitory
effect on
the plasma and hepatic lipid peroxidation and increased the hepatic catalase
activity in high-cholesterol fed rabbits.
23. J Cardiovasc Pharmacol. 2001 Dec;38(6):947-55.
Naringin has an antiatherogenic effect with the inhibition of intercellular
adhesion molecule-1 in hypercholesterolemic rabbits.
Choe SC, Kim HS, Jeong TS, Bok SH, Park YB.
Department of Internal Medicine, Soonchunhyang University Bucheon Hospital,
Bucheon, Korea.
Naringin, a bioflavonoid found in citrus fruit peel, is known to have
an
antioxidative effect, but its effect on atherosclerosis has not been studied.
This study evaluated the effect of naringin on blood lipid levels and
aortic
fatty streaks, and its action mechanism in hypercholesterolemic rabbits.
Male
New Zealand white rabbits were fed a 0.25% cholesterol diet and divided
into an
untreated group (n = 4), a naringin-treated group (n = 5; 500 mg/kg per
day),
and a lovastatin-treated group (n = 5; 20 mg/kg per day). After 8 weeks,
blood
was sampled and analyzed biochemically. Aorta and liver were harvested
and
examined histologically. Cholesterol level in rabbits fed the 0.25% cholesterol
diet reached 17 times normal and decreased in the rabbits fed naringin
and
lovastatin, whose effects were not statistically significant (p > 0.05).
However, both naringin and lovastatin effectively decreased the area of
fatty
streak in thoracic aorta on macroscopic analysis (p < 0.05) and significantly
reduced subintimal foam cell infiltration on microscopic morphometry (p
< 0.05).
These foam cells were macrophages on immunohistochemical analysis. Naringin
treatment inhibited hypercholesterolemia-induced intercellular adhesion
molecule-1 (ICAM-1) expression on endothelial cells. Hypercholesterolemia
caused
fatty liver and elevation of liver enzymes, which was prevented by naringin
but
not by lovastatin. Naringin significantly reduced fatty streak formation
and
neointimal macrophage infiltration and also inhibited the expression of
ICAM-1
in endothelial cells, suggesting that suppression of ICAM-1 contributed
to the
antiatherogenic effect. Naringin, unlike lovastatin, has a hepatoprotective
action.
24. Ann Nutr Metab. 2001;45(5):193-201.
Effect of naringin supplementation on cholesterol metabolism and antioxidant
status in rats fed high cholesterol with different levels of vitamin E.
Choi MS, Do KM, Park YS, Jeon SM, Jeong TS, Lee YK, Lee MK, Bok SH.
Department of Food Science and Nutrition, Kyungpook National University,
1370
Yank-Suk Dong Pak-Ku, 702-701, Taegu, Korea. mschoi@knu.ac.kr
Some bioflavonoids are potent antioxidants and have pharmacological effects
similar to those of vitamin E. The interactive effect of naringin and
vitamin E
was studied with respect to cholesterol metabolism and antioxidant status.
Naringin supplementation (0.1%, wt/wt) with comparable levels of vitamin
E was
given to rats with a high-cholesterol (1%, wt/wt) diet for 5 weeks. The
amount
of vitamin E included in naringin-free and naringin diets was a low (low-E)
and
a normal (normal-E) level. The naringin supplementation significantly
lowered
the concentrations of plasma cholesterol and triglyceride compared to
the
naringin-free group in low vitamin E-fed rats. HMG-CoA reductase activity
was
significantly lowered by naringin supplementation within both the low-vitamin
E
group (794.64 +/- 9.87 vs. 432.18 +/- 12.33 pmol/min/mg protein, mean
+/- SE; p
< 0.05) and normal-vitamin E group (358.82 +/- 11.4 vs. 218.22 +/-
9.47
pmol/min/mg protein, mean +/- SE; p < 0.05) compared to each of the
naringin-free group. The HMG-CoA reductase activity was also significantly
lowered by increased dietary vitamin E when compared within the naringin
and
naringin-free group, respectively. Neither dietary naringin nor vitamin
E did
significantly change the activities of hepatic antioxidant enzymes and
plasma
thiobarbituric acid-reactive substance level. These data indicate that
naringin
lowers the plasma lipid concentrations when the dietary vitamin E level
is low.
The HMG-CoA reductase-inhibitory effect of naringin was more potent when
dietary
vitamin E was at a normal level. These data may contribute to understanding
the
interactive effect of naringin and vitamin E on cholesterol biosynthesis
in
high-cholesterol-fed rats. Copyright 2001 S. Karger AG, Basel
25. Biochem Biophys Res Commun. 2001 Jun 15;284(3):681-8.
Anti-atherogenic effect of citrus flavonoids, naringin and naringenin,
associated with hepatic ACAT and aortic VCAM-1 and MCP-1 in high cholesterol-fed
rabbits.
Lee CH, Jeong TS, Choi YK, Hyun BH, Oh GT, Kim EH, Kim JR, Han JI, Bok
SH.
Genetic Resources Center, Korea Research Institute of Bioscience and
Biotechnology, Taejon 305-600, Korea.
The anti-atherogenic effects of the citrus flavonoids, naringin and naringenin,
were evaluated in high cholesterol-fed rabbits. At 3 months of age, 30
male New
Zealand White (NZW) rabbits were divided into three groups (n = 10 per
group).
The rabbits were fed a 1% cholesterol diet alone (control group) or a
diet
supplemented with either 0.1% naringin or 0.05% naringenin for 8 weeks.
The
plasma lipoprotein levels, total cholesterol, triglyceride, and high-density
lipoprotein showed no significant differences in the control and experimental
groups. Hepatic acyl-CoA:cholesterol acyltransferase (ACAT) activity was
slightly low in naringin (5.0%)- and naringenin (15.0%)-fed rabbits, compared
to
control group. The aortic fatty streak areas were significantly lower
in both
the naringin (19.2 +/- 5.6%)- and naringenin (18.1 +/- 6.5%)-supplemented
groups
than in the control group (60.4 +/- 14.0%). The expression levels of vascular
cell adhesion molecule-1 (VCAM-1) and monocyte chemotactic protein-1 (MCP-1),
by
semiquantitative RT-PCR analysis of the thoracic aorta, were significantly
lower
in the flavonoids supplemented groups than in the control group. These
results
suggest that the anti-atherogenic effect of the citrus flavonoids, naringin
and
naringenin, is involved with a decreased hepatic ACAT activity and with
the
downregulation of VCAM-1 and MCP-1 gene expression. Copyright 2001 Academic
Press.
26. Int J Vitam Nutr Res. 1999 Sep;69(5):341-7.
Hypocholesterolemic effect of naringin associated with hepatic cholesterol
regulating enzyme changes in rats.
Shin YW, Bok SH, Jeong TS, Bae KH, Jeoung NH, Choi MS, Lee SH, Park YB.
Korea Research Institute of Bioscience & Biotechnology, KIST, Yusong,
Taejon,
Korea.
The effects of the citrus bioflavonoid naringin were tested by using
it as a
supplement in a high-cholesterol diet. Male rats were fed for 42 days
with a 1%
(wt/wt) high cholesterol diet either with or without naringin-supplementation
(0.1%, wt/wt) to study the effect on plasma lipid levels, hepatic lipid
contents, hepatic enzyme activity, and the excretion of fecal neutral
sterols.
Naringin did not significantly alter the levels of plasma triglycerides,
however, the levels of plasma cholesterol (3.80 +/- 0.31 mmol/L vs. 2.61
+/-
0.30 mmol/L, mean +/- SE; p < 0.05) and hepatic cholesterol (70.3 +/-
4.3 mg/g
vs. 54.3 +/- 3.8 mg/g, mean +/- SD; p < 0.05) were significantly lowered
compared to those of the control. HMG-CoA reductase (2487.0 +/- 210.0
pmole/min/mg vs. 1879.0 +/- 236.0 pmole/min/mg, mean +/- SE; p < 0.05)
and ACAT
(806.0 +/- 105.0 pmole/min/mg vs. 643.0 +/- 80.0 pmole/min/mg, mean +/-
SE; p <
0.05) activities were both substantially lower in the naringin-supplemented
group than in the control. The naringin supplementation markedly decreased
the
excretion of fecal neutral sterols (204.7 +/- 28.5 mg/day) compared to
the
control (521.9 +/- 53.9 mg/day). The combination of the inhibited HMG-CoA
reductase (-24.4%) and ACAT (-20.2%) activities as a result of naringin
supplementation could account for the decrease of fecal neutral sterols.
HISTAMINE **
27. Acta Physiol Pharmacol Bulg. 1980;6(2):70-5.
Flavonoids with antioxidant action (naringin and rutin) and the release
of
mastocytic and nonmastocytic histamine.
Lambev I, Belcheva A, Zhelyazkov D.
In view of the data about the antioxidant mechanism of the membrane-stabilizing
action of the bioflavonoids, the participation of this mechanism in the
release
of histamine as well is assumed to be possible. Experiments are carried
out on
35 male albino rats. The effect of the flavonoids naringin and rutin on
the
level of mastocytic and nonmastocytic histamine is studied, as well as
on its
release induced by compound 48/80 (2 mg/kg i. p.). The substances are
applied
intraperitonealy in doses of 200 mg/kg; corresponding to 10% DL50. The
histamine
content is determined fluorimetrically by the method of Schore et al.
(1959).
The results show that naringin and rutin have no effect on the levels
of
mastocytic and nonmastocytic histamine. They prevent the release of mastocytic
histamine, induced by compound 48/80.
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