Naringenin


Naringenin is a flavorless, colorless flavanone, a type of flavonoid. It is the predominant flavanone in grapefruit, and is found in a variety of fruits and herbs.

Structure

Naringenin has the skeleton structure of a flavanone with three hydroxy groups at the 4', 5, and 7 carbons. It may be found both in the aglycol form, naringenin, or in its glycosidic form, naringin, which has the addition of the disaccharide neohesperidose attached via a glycosidic linkage at carbon 7.

Chirality

Like the majority of flavanones, naringenin has a single chiral center at carbon 2, resulting in enantiomeric forms of the compound. The enantiomers are found in varying ratios in natural sources. Racemization of S-naringenin has been shown to occur fairly quickly. Naringenin has been shown to be resistant to enatiomerization over pH 9-11.
Separation and analysis of the enantiomers has been explored for over 20 years, primarily via high-performance liquid chromatography on polysaccharide-derived chiral stationary phases. There is evidence to suggest stereospecific pharmacokinetics and pharmacodynamics profiles, which has been proposed to be an explanation for the wide variety in naringenin's reported bioactivity.

Bioavailability

This bioflavonoid is difficult to absorb on oral ingestion. In the best-case scenario, only 15% of ingested naringenin will get absorbed in the human gastrointestinal tract.
The naringenin-7-glucoside form seems less bioavailable than the aglycol form.
Grapefruit juice can provide much higher plasma concentrations of naringenin than orange juice. Also found in grapefruit is the related compound kaempferol, which has a hydroxyl group next to the ketone group.
Naringenin can be absorbed from cooked tomato paste. There is 253 mg of naringenin in 10 grams of tomato paste.

Metabolism

The enzyme naringenin 8-dimethylallyltransferase uses dimethylallyl diphosphate and --naringenin to produce diphosphate and 8-prenylnaringenin.

Biodegradation

Cunninghamella elegans, a fungal model organism of the mammalian metabolism, can be used to study the naringenin sulfation.

Potential biological effects

Inhibitory activity

Naringenin has been shown to have an inhibitory effect on the human cytochrome P450 isoform CYP1A2, which can change pharmacokinetics in a human host of several popular drugs in an adverse manner, even resulting in carcinogens of otherwise harmless substances. The National Research Institute of Chinese Medicine in Taiwan conducted experiments on the effects of the grapefruit flavanones naringin and naringenin on CYP450 enzyme expression. Naringenin proved to be a potent inhibitor of the benzopyrene metabolizing enzyme benzopyrene hydroxylase in experiments in mice.

Alzheimer's disease

Naringenin is being researched as a potential treatment for Alzheimer's disease. Naringenin has been demonstrated to improve memory and reduce amyloid and tau proteins in a study using a mouse model of Alzheimer's disease. The effect is believed to be due to a protein present in neurons known as CRMP2 that naringenin binds to.

Antibacterial, antifungal, and antiviral

Naringenin's potential antibacterial and antifungal behaviour has been investigated. In 1987, it was reported that naringenin had no antibacterial activity against Staphylococcus epidermidis. This finding was not replicated in a 2000 study in which naringenin was shown to indeed have an antimicrobial effect on S. epidermidis, as well as Staphylococcus aureus, Bacillus subtilis, Micrococcus luteus, and Escherichia coli. Further research has added evidence for antimicrobial effects against Lactococcus lactis, lactobacillus acidophilus, Actinomyces naeslundii, Prevotella oralis, Prevotella melaninogencia, Porphyromonas gingivalis, as well as yeasts such as Candida albicans, Candida tropicalis, and Candida krusei. There is also evidence of antibacterial effects on H. pylori, though naringenin has not been shown to have any inhibition on urease activity of the microbe.
Naringenin has also been shown to reduce hepatitis C virus production by infected hepatocytes in cell culture. This seems to be secondary to naringenin's ability to inhibit the secretion of very-low-density lipoprotein by the cells. The antiviral effects of naringenin are currently under clinical investigation. Reports of antiviral effects on polioviruses, HSV-1 and HSV-2 have also been made, though replication of the viruses has not been inhibited.

Anti-inflammatory

Despite evidence of anti-inflammatory activity of naringin, the anti-inflammatory activity of naringenin has been observed to be poor to nonexistent.

Antioxidant

Naringenin has been shown to have significant antioxidant properties. It has been shown to reduce oxidative damage to DNA in vitro and in animal studies.

Anticancer

Cytotoxicity has been induced reportedly by naringenin in cancer cells from breast, stomach, liver, cervix, pancreas, and colon tissues, along with leukaemia cells. The mechanisms behind inhibition of human breast carcinoma growth have been examined, and two theories have been proposed. The first theory is that naringenin inhibits aromatase, thus reducing growth of the tumor. The second mechanism proposes that interactions with estrogen receptors is the cause behind the modulation of growth. New derivatives of naringenin were found to be active against multidrug-resistant cancer.

Antiadipogenic activity and cardioprotective effects

Naringenin has been reported to induce apoptosis in preadipocytes.
Naringenin seems to protect LDLR-deficient mice from the obesity effects of a high-fat diet.
Naringenin lowers the plasma and hepatic cholesterol concentrations by suppressing HMG-CoA reductase and ACAT in rats fed a high-cholesterol diet.

Other effects

Naringenin also produces BDNF-dependent antidepressant-like effects in mice.
In 2006 it was shown to increase the mRNA expression levels of two DNA repair enzymes, DNA pol beta and OGG1, specifically in prostate cancer cells.
Like many other flavonoids, naringenin has been found to possess weak activity at the opioid receptors. It specifically acts as a non-selective antagonist of all three opioid receptors, albeit with weak affinity.