Health effects of natural phenols and polyphenols

Because of the large structural diversity of dietary polyphenols, it is difficult to assert specific health effects from such ubiquitous substances. Their antioxidant activities in chemical and biological assays are undisputed, and many are associated with the health-promoting effects of fruits and vegetables, but to what extent these effects apply to entire organisms, and clinical outcomes in human disease in particular, remains a controversially discussed topic in nutrition science and disease prevention.

Health effects
A review published in 2012 found growing consensus for the hypothesis that the specific intake of food and drink containing relatively high concentrations of flavonoids may play a meaningful role in reducing the risk of cardiovascular disease (CVD). The reviewers stated that research to date had been of poor quality and the large and rigorous trials are needed better to study the science, and to investigate possible adverse effects associated with excessive polyphenol intake: currently a lack of knowledge about safety suggests that polyphenol levels should not exceed that which occurs in a normal diet.

Toxicity
Toxicological concerns from dietary polyphenols have been voiced. They are unrelated to the acute toxicity of the phenols used in chemical industries. They are based on a number of in-vitro assays on the mutagenic and genotoxic properties of flavonols, such as quercetin. However, natural phenols and polyphenols are not classified as carcinogens. Their acute toxicity in humans and herbivores is generally very low due to their poor bioavailability. Tannins can have anti-feeding effects in livestock and interfere with nutrient absorption. This applies in particular to the astringent polyphenols and much less to the cinnamic and caffeic acid derivatives.

Bioavailability
Questions on the relationship between health benefits and polyphenols generally revolve around bioavailability. Gallic acid and isoflavones are the most well-absorbed phenols, followed by catechins (flavan-3-ols), flavanones, and quercetin glucosides, but with different kinetics. The least well-absorbed phenols are the proanthocyanidins, galloylated tea catechins, and anthocyanins.

Antioxidant activity
As interpreted by the Linus Pauling Institute and the European Food Safety Authority (EFSA), dietary flavonoids have little or no direct antioxidant food value following digestion. Unlike controlled test tube conditions, the fate of natural phenols in vivo shows they are poorly conserved (less than 5%), with most of what is absorbed existing as chemically-modified metabolites destined for rapid excretion.

In vitro effects
Mainly from in vitro studies, natural phenols have been reported to have antimicrobial, antiviral, anti-inflammatory, and vasodilatory actions.

Epigallocatechin gallate (EGCG), a flavanol found in tea, may have an effect on cancer by inhibiting DNA methyltransferase activity. It has been shown to reduce reactive oxygen species levels in vitro.

The natural phenol resveratrol inhibits occurrence and/or growth of experimental tumors.

Mainly from in vitro studies, polyphenols have been reported to have antimicrobial, antiviral, antimutagenic, anticarcinogenic, antiproliferative and vasodilatory actions. Polyphenols may have antibacterial activity useful to combat tooth decay caused by Streptococcus mutans. Polyphenols are listed as nootropics purported to improve mental functions such as cognition, memory, intelligence, motivation, attention and concentration.

Phenolic-rich extracts from edible marine algae may have an anti-proliferative effect on colon cancer cells and an anti-diabetic effect by means of interactions of phlorotannins with α-amylase and α-glucosidase in the gut. Molecular mechanisms possibly underlying activities of anti-inflammatory polyphenols would be down-regulation of COX-2 and iNOS through suppression of NF-κB activation.

In vivo effects in model species
Natural phenols such as resveratrol activate human SIRT1, extend the lifespan of budding yeast, Saccharomyces cerevisiae, and may be sirtuin-activating compounds. Other examples of such products are butein, piceatannol, isoliquiritigenin, fisetin, and quercetin. Longevity increased by resveratrol was demonstrated in Caenorhabditis elegans and Drosophila melanogaster. This longevity increase may be due to a caloric restriction effect. Resveratrol also increases the lifespan of vertebrates as has been demonstrated in short-lived fish, Nothobranchius furzeri.

Other experiments on Drosophila melanogaster indicate that natural phenols (gallic acid, ferulic acid, caffeic acid, coumaric acid, propyl gallate, epicatechin, epigallocatechin, and epigallocatechin gallate) may influence mechanisms related to Parkinson's disease. Quercetin and rutin act against scopolamine-induced memory impairment in zebrafish, Danio rerio.

Longevity increased by polyphenols was demonstrated in Caenorhabditis elegans. This longevity increase may be due to a caloric restriction effect.

Grape seed polyphenolic extract may improve the phenotype in a Drosophila model of tauopathy.

Polyphenol-enriched extract can attenuate food allergy symptoms in sensitized mice.

Neonatal effects
Many natural phenols, like the flavonoids, were found to be strong topoisomerase inhibitors in vitro, some of them were tested in vivo with similar results. Those substances share the properity with some chemotherapeutic anticancer drugs such etoposide and doxorubicin. When tested some natural phenols induced DNA mutations in MLL gene, which are common findings in neonatal acute leukemia. The DNA changes were highly increased by treatment with flavonoids in cultured blood stem cells. Maternal high flavonoid content diet is suspected to increase risk of particularly acute myeloid leukemia in neonates. Natural phenols have both anticarcinogenic - proapoptotic effect and a carcinogenic, DNA damaging, mutagenic potential. Adults seem to rapidly metabolize most of phenols, so toxic, mutagenic effect may not be pronounced in regular low doses intaken with food. Some natural phenols - ex. EGCG were found to rapidly induce detoxyfying Nrf2 transcription factor activity which seems to be responsible for observed beneficial, antioxidative effects of the substances and also leads to rapid degradation of the phenolic molecules. However human embryos detoxification system is not mature enough to deal with phenols, which have possibility to cross the placenta barier. High intake of flavonoid compounds during pregnancy is suspected to increase risk of neonatal leukemia. Therefore "bioflavonoid" supplements should be not used by pregnant women.

An open, unblinded clinical study of 51 subjects published in 2012 showed that maternal ingestion of polyphenol-rich foods in the third trimester of pregnancy may cause constriction of a blood vessel in the fetus that bypasses the non-functioning lungs. Constriction of this vessel in the fetus is a risk factor for pulmonary hypertension in the infant. Maternal use of NSAIDs in the third trimester are a known risk factor constriction of this vessel in the fetus, and the investigators hypothesized that natural polyphenols might act similarly to NSAIDs.

Phytoestrogenic effect
Phytoestrogens mainly belong to a large group of substituted natural phenolic compounds : the coumestans, prenylflavonoids and isoflavones. Bisphenol A, a synthetic phenolic compound, is an endocrine disruptor, which can mimic the body's own hormones and may lead to negative health effects.

Carcinogenicity
The Carcinogenic Potency Project, which is a part of the US EPA's Distributed Structure-Searchable Toxicity (DSSTox) Database Network, has been systemically testing the carcinogenicity of chemicals, both natural and synthetic, and building a publicly available database of the results since about 1980. At this time, none of the dietary phenols and polyphenols are classified as carcinogens. Some polyphenols, particularly from the flavan-3-ol (catechin-type), have both anticarcinogenic-proapoptotic and mutagenic effects. The DNA changes were increased by treatment with flavonoids in cultured blood stem cells. Some natural polyphenols share the properties of some anticancer drugs such as etoposide and doxorubicin while other polyphenols may induce DNA mutations in the MLL gene, which are common findings in neonatal acute leukemia.

Anemia
Polyphenols bind with nonheme iron (e.g. from plant sources) in vitro in model systems, possibly reducing its absorption especially in vegetarian nutrition.