Naringenin benefit and review, clinical trials by Ray Sahelian, M.D.

Naringenin is one of the most abundant citrus bioflavonoids. A high-

vegetable diet with various fruits and vegetables daily including on average
one glass of orange juice, one-half orange and one-half mandarin provides
130 mg of hesperetin and 30 mg of naringenin. Naringenin has been shown
to inhibit in vitro growth of in human cancer cells.

Naringenin has anti-oxidant and anti-tumor activity. Naringinen may play a

role in cancer prevention or perhaps treatment, Heart disease prevention,
hypertension, improving circulation, and Alzheimer's disease.

Eyesight Rx with Naringenin

Supports Healthy Vision
Developed by Ray Sahelian, M.D.

Unlike some vision products that provide nutrients and herbs

for long term healthy vision support, and prevention of visual
impairment, but don't seem to have much of an immediate
effect on visual acuity, Eyesight Rx was formulated to provide a
quick and noticeable vision improvement within hours or days
of use.

Reports from Eyesight Rx users indicate enhanced clarity of

vision, colors being brighter, better focus, and overall improvement in
close and distance vision.

Vitamin C - (Ascorbic acid)

Citrus bioflavonoids (eriocitrin, hesperidin, flavonols, flavones, flavonoids,
naringenin, and quercetin)
Mixed carotenoids (alpha carotene, astaxanthin, beta carotene,
cryptoxanthin, Lutein, Lycopene, Zeaxanthin)
Bilberry extract (Vaccinium myrtillus)
Eyebright extract (Euphrasia officianales)
Jujube extract (Zizyphus jujube)
Ginkgo biloba (Ginkgo biloba)
Suma extract (Pfaffia paniculata)
Mucuna pruriens extract (Cowhage)
Cinnamon (Cinnamomum zeylanicum)
Lycium berry extract (Lycium Barbarum) - also known as Goji Berry
Alpha Lipoic Acid antioxidant

Role in atherosclerosis or hardening of the arteries

Naringenin decreases progression of atherosclerosis by improving
dyslipidemia in high-fat-fed low-density lipoprotein receptor-null mice.
Arterioscler Thromb Vasc Biol. 2010 Apr; Mulvihill EE, Assini JM, Sutherland BG,
DiMattia AS, Khami M, Koppes JB, Sawyez CG, Whitman SC, Huff MW.
Vascular Biology Group, Robarts Research Institute, The University of Western
Ontario, 100 Perth Dr, London, ON, Canada.
Naringenin is a citrus flavonoid that potently inhibits the assembly and
secretion of apolipoprotein B100-containing lipoproteins in cultured
hepatocytes and improves the dyslipidemia and insulin resistance in a
mouse model of the metabolic syndrome. In the present study, we used
low-density lipoprotein receptor-null mice fed a high-fat diet (Western,
TD96125) to test the hypothesis that naringenin prevents atherosclerosis.
These in vivo studies demonstrate that the citrus flavonoid naringenin
ameliorates the dyslipidemia in Western-fed low-density lipoprotein
receptor-null mice, leading to decreased atherosclerosis; and suggests a
potential therapeutic strategy for the hyperlipidemia and increased risk of
atherosclerosis associated with insulin resistance.

Naringenin Research study

Naringenin attenuates cisplatin nephrotoxicity in rats.
Life Sci. 2005 Mar 18;76(18):2125-35. Epub 2005 Jan 22.
The effect of naringenin, a naturally occurring citrus flavanone, on the
acute nephrotoxicity produced by cisplatin (7 mg/kg, i.v.) was investigated
in the rat. Oral administration of NAR (20 mg/kg/day) for 10 days, starting 5
days before cisplatin single i.v. injection, produced significant protection of
renal function. Naringenin reduced the extent of cisplatin-induced
nephrotoxicity, as evidenced by significant reduction in serum urea and
creatinine concentrations, decreased polyuria, reduction in body weight
loss, marked reduction in urinary fractional sodium excretion and
glutathione S-transferase (GST) activity, and increased creatinine
clearance. Cisplatin-induced alterations in renal cortex lipid peroxides and
GST activity were markedly improved by Naringenin. Cisplatin-induced
alterations in renal cortex antioxidant defense system were greatly
prevented by Naringenin. In cisplatin-Naringenin combined treatment
group, antioxidant enzymes namely superoxide dismutase (SOD),
glutathione peroxidase (GSH-Px), and catalase (CAT) were significantly
increased to 54.5, 30.3 and 35.6%, respectively compared to cisplatin
treated group. Platinum renal content was not affected by Naringenin
treatment. The results provide further insight into the mechanisms of
cisplatin-induced nephrotoxicity and confirm the antioxidant potential of
Naringenin.

Inhibitory effects of naringenin on tumor growth in human cancer cell lines

and sarcoma S-180-implanted mice.
Biol Pharm Bull. 2005 Mar;28(3):527-30.
We have investigated the effect of naringenin on tumor growth in various
human cancer cell lines and sarcoma S-180-implanted mice. NGEN showed
cytotoxicity in cell lines derived from cancer of the breast (MCF-7, MDA-
MB-231), stomach (KATOIII, MKN-7), liver (HepG2, Hep3B, Huh7), cervix
(Hela, Hela-TG), pancreas (PK-1), and colon (Caco-2) as well as leukemia
(HL-60, NALM-6, Jurkat, U937). Naringenin -induced cytotoxicity was low in
Caco-2 and high in leukemia cells compared to other cell lines. Naringenin
dose-dependently induced apoptosis, with hypodiploid cells detected in
both Caco-2 and HL-60 by flow cytometric analysis. In vivo, Naringenin
inhibited tumor growth in sarcoma S-180-implanted mice, following
intraperitoneal or peroral injection once a day for 5 d. Naringin (NG) also
inhibited tumor growth by peroral injection but not intraperitoneal injection.
Naringenin, one of the most abundant flavonoids in citrus fruits, may have
a potentially useful inhibitory effect on tumor growth.

Structure-activity relationship (SAR) between some natural flavonoids and

ocular blood flow in the rabbit.
J Ocul Pharmacol Ther. 2004 Feb;20(1):35-42.
Flavonoids with two to five hydroxy groups, with or without sugar, and/or
methoxy groups were studied on their effects to affect ocular blood flow.
Colored microsphere technique was used to determine the ocular blood
flow in rabbit eyes. RESULTS: Flavonoids with three free hydroxy (OH)
groups seemed to produce the optimal effects in increasing ocular blood
flow (naringenin and hesperitin, Pfalts and Bauer, Waterbury, CT). Whether
the OH groups are below three (naringenin, hesperitin, Pfalts and Bauer,
Waterbury, CT) or above four (Quercetin, Pfalts and Bauer, Waterbury, CT),
they produced no effects on the ocular blood flow. When OH groups are
four (rutin, Aldrich, Milwaukee, WI), it produced mixed effects on ocular
blood flow. The attachment of rutinose and/or methoxy group in the
structure did not affect the ocular blood flow one way or the other. The
ocular blood flow is increased significantly by the number of OH group in
the molecule, with three the best to increase the ocular blood flow.

Naringenin from Citrus junos has an inhibitory effect on

acetylcholinesterase and a mitigating effect on amnesia.
Dement Geriatr Cogn Disord. 2004;17(3):151-7.
This study was performed to identify safe and more effective
acetylcholinesterase (AChE) inhibitors in the treatment of Alzheimer's
disease. The total methanol extract of Citrus junos had a significant
inhibitory effect on AChE in vitro. By sequential fractionation of C.junos,
the active component was finally identified as naringenin. Naringenin
inhibited AChE activity in a dose-dependent manner. In this study, we also
evaluated the anti-amnesic activity of naringenin, a major flavanone
constituent isolated from C. junos, in vivo using ICR mice with amnesia
induced by scopolamine (1 mg/kg body weight). Naringenin, when
administered to mice at 4.5 mg/kg body weight, significantly ameliorated
scopolamine-induced amnesia as measured in both the passive avoidance
and the Y-maze test. These results suggest that naringenin may be a useful
chemopreventive agent against Alzheimer's disease.
The citrus-derived flavonoid naringenin exerts uterotrophic effects in
female mice at human relevant doses.
Basic Clin Pharmacol Toxicol. 2004 Jan;94(1):30-6.
Gavage administration of the citrus flavonoid naringenin, 3',4,5,7-
tetrahydroxyflavanon for 4 consecutive days, to immature female mice
(postnatal day 17-20) at 4 or 100 mg/kg b.wt. significantly increased uterine
weights 3 and 4 times, respectively. Analysis of uterine oestrogen receptor
alpha revealed that naringenin significantly increased the cytosolic
concentration of oestrogen receptor alpha, whereas in nuclei the oestrogen
receptor alpha concentration was significantly decreased as compared to
the solvent control. This was in contrast to the positive control 17 beta-
oestradiolacetate which acted as a true oestrogen by increasing the
concentration of both total and nuclear oestrogen receptor alpha. Both
naringenin and 17 beta-oestradiolacetate, however, significantly, induced
nuclear oestrogen receptor alpha in the liver, suggesting a tissue specific
effect of naringenin on oestrogen receptor alpha distribution. In order to
investigate the tissue levels at which the uterotrophic effect was observed,
the distribution of an oral dose of tritiated naringenin (4 mg/kg) was
investigated in 3-week-old female mice. The radioactivity content (ng
naringenin equivalents/g tissue) was found to be highest in the
gastrointestinal-tract, followed by the kidneys and liver. Uterus and ovaries
were also found to contain relatively high and approximately equal
amounts of naringenin. The concentration of naringenin in uterus and
ovaries was found to be ten times higher as compared to the mammary
tissue. The urinary excretion of more than 25% of the administered dose,
within 8 hr after dosing indicated that naringenin is absorbed extensively in
mice. The plasma concentration of 0.5 microM found in the present study is
similar to the peak plasma concentration of naringenin (0.6 microM)
observed in man following ingestion of 400-760 ml of orange juice (Erlund
et al. 2001). This could be taken to suggests that ingestion of orange juice
and other citrus fruits and juices may give rise to sufficiently high tissue
levels of naringenin in man to exert a biological effect.

The variable effect on proliferation of a colon cancer cell line by the citrus
fruit flavonoid Naringenin.
Colorectal Dis. 2003 Mar;5(2):149-52.
Naringenin, a naturally occurring flavonoid found in citrus fruits, is known
to have anticarcinogenic properties. We have examined the effect of
Naringenin on cell proliferation of an HT-29 colon cancer cell line. HT-29
colon cancer cells were cultured in 96-well tissue culture plates. Naringenin
concentrations ranging from 0.02 to 2.85 mmol were added to the wells of
the Test group. The Control group contained all the elements present in the
Test group with the exception of Naringenin. Cell proliferation was
measured by colourimetric assay using the 2% WST-1 cell proliferation kit.
Significant inhibition of cell proliferation was observed in HT29 colon
cancer cells exposed to Naringenin at doses greater than 0.71 mmol. These
results suggest a potential role for citrus fruits as a source of
chemoprotective agents for colon cancer.

Interaction between flavonoids and the blood-brain barrier: in vitro studies.

J Neurochem. 2003 April.
There is considerable current interest in the neuroprotective effects of
flavonoids. This study focuses on the potential for dietary flavonoids, and
their known physiologically relevant metabolites, to enter the brain
endothelium and cross the blood-brain barrier (BBB) using well-
established in vitro models (brain endothelial cell lines and ECV304
monolayers co-cultured with C6 glioma cells). We report that the citrus
flavonoids, hesperetin, naringenin and their relevant in vivo metabolites, as
well as the dietary anthocyanins and in vivo forms, cyanidin-3-rutinoside
and pelargonidin-3-glucoside, are taken up by two brain endothelial cell
lines from mouse (b.END5) and rat (RBE4). In both cell types, uptake of
hesperetin and naringenin was greatest, increasing significantly with time
and as a function of concentration. In support of these observations we
report for the first time high apparent permeability (Papp) of the citrus
flavonoids, hesperetin and naringenin, across the in vitro BBB model
(apical to basolateral) relative to their more polar glucuronidated
conjugates, as well as those of epicatechin and its in vivo metabolites, the
dietary anthocyanins and to specific phenolic acids derived from colonic
biotransformation of flavonoids. The results demonstrate that flavonoids
and some metabolites are able to traverse the BBB, and that the potential
for permeation is consistent with compound lipophilicity.

Comparison of antioxidant effects of naringin and probucol in cholesterol-

fed rabbits.
Clin Chim Acta. 2002 Mar;317(1-2):181-90.
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). 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. 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.

Flavanone absorption after naringin, hesperidin, and citrus administration.

Clin Pharmacol Ther. 1996 Jul;60(1):34-40.
Disposition of citrus flavonoids was evaluated after single oral doses of
pure compounds (500 mg naringin and 500 mg hesperidin) and after
multiple doses of combined grapefruit juice and orange juice and of once-
daily grapefruit. Cumulative urinary recovery indicated low bioavailability
( < 25%) of naringin and hesperidin. The aglycones naringenin and
hesperitin were detected in urine and plasma. After juice administration, we
detected naringenin, hesperitin, and four related flavanones, tentatively
identified as monomethoxy and dimethoxy derivatives. These
methoxyflavanones appear to be absorbed from juice. Absorbed citrus
flavanones may undergo glucuronidation before urinary excretion.

Naringenin supplement questions

Q. Please advise me as to how effective oral supplementation of naringenin
is. How much is absorbed by the GI tract?
A. As of 2008, we are not aware of human research with naringenin
supplements to determine its benefits and the absorption rate. Naringenin
from foods is quite well absorbed.

Plasma concentrations of the flavonoids hesperetin, naringenin and

quercetin in human subjects following their habitual diets, and diets high
or low in fruit and vegetables.
Eur J Clin Nutr. 2002 Sepember. Biomarker Laboratory, National Public Health
Institute (KTL), Helsinki, Finland. To determine the fasting plasma
concentrations of quercetin, hesperetin and naringenin in human subjects
consuming their habitual diets, and diets either high or low in fruit and
vegetables. To investigate whether plasma concentrations of flavanones
can serve as biomarkers of their intake. This was a cross-over, strictly
controlled dietary intervention consisting of a 2 week baseline period, and
two 5 week dietary periods with a 3 week wash-out period in between. The
low-vegetable diet contained few fruit and vegetables and no citrus fruit.
The high-vegetable diet provided various fruits and vegetables daily
including on average one glass of orange juice, one-half orange and one-
half mandarin. The high-vegetable diet provided 132 mg of hesperetin and
29 mg of naringenin. The low-vegetable diet contained no flavanones. After
the high-vegetable diet, hesperetin and naringenin were detectable in 54
and 22% of all samples. Quercetin was detectable in nearly all samples
after all study periods. Hesperetin, naringenin and quercetin are
bioavailable from the diet, but the plasma concentrations of hesperetin and
naringenin are poor biomarkers of intake.

I am interested in the naringenin content in Eyesight Rx product (per

capsule in mg).
We use a bioflavonoid complex that has several substances in it and it
does not say the specific amount.

I am attempting to locate a source of naringenin but have not had any

success. I would prefer a purified source from a chemical company, but
again, I have not been able to identify any biochemical supply house that
offers this product. I would be most appreciative if you could help me out.
Even a dietary supplement would be a good start. I am wanting to test its
effects on human liver cancer cells. Please disregard my prior e-mail about
locating a source. I just found that Sigma Aldrich sells a purified source.

We are a group of middle school students participating in the First Lego

League robotics competition. As part of the competition we are researching
a topic in Biomedicine and trying to find a unique solution to a key issue in
the body. As part of the effort we are to identify a problem as it relates to a
specific body part. Our research led us to the negative impact of the fat and
sugars in fast food on the pancreas. The high sugar contents of most fast
food over stimulate the pancreas causing a peak in sugar, follow by a rapid
drop, leaving the individual tired and some cases hungry. This cycle over-
stimulates the pancreas and the false sense of repetitive cycle causes
obesity and more serious diseases such as diabetes and cancer. To break
this cycle, we found that narigenin, a chemical in citrus peels, counteracts
the bad effects of fat and sugar on the pancreas.
One nutrient or substance alone is not able to counteract the deleterious
effect of fats and sugars, there is no substitute for a healthy diet, there are
hardly any human studies with naringenin as a pill taken orally so it is not
known what kind of overall benefit or side effect it will have when taken
alone as a supplement as opposed to being present and consumed in
combination with other substances found naturally in fruits.