Flavonoids: Structure–Function and Mechanisms of Action and Opportunities for Drug Development
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Toxicological Research Toxicol Res. eISSN 2234-2753 https://doi.org/10.1007/s43188-020-00080-z pISSN 1976-8257 INVITED REVIEW Flavonoids: structure–function and mechanisms of action and opportunities for drug development Stephen Safe1 · Arul Jayaraman2 · Robert S. Chapkin3 · Marcell Howard1 · Kumaravel Mohankumar1 · Rupesh Shrestha4 Received: 10 November 2020 / Accepted: 4 December 2020 © Korean Society of Toxicology 2021 Abstract Flavonoids are polyphenolic phytochemicals produced in fruits, nuts and vegetables and dietary consumption of these structurally diverse compounds is associated with multiple health benefts including increased lifespan, decreased cardio- vascular problems and low rates of metabolic diseases. Preclinical studies with individual favonoids demonstrate that these compounds exhibit anti-infammatory and anticancer activities and they enhance the immune system. Their efectiveness in both chemoprevention and chemotherapy is associated with their targeting of multiple genes/pathways including nuclear receptors, the aryl hydrocarbon receptor (AhR), kinases, receptor tyrosine kinases and G protein-coupled receptors. However, despite the remarkable preclinical activities of favonoids, their clinical applications have been limited and this is due, in part, to problems in drug delivery and poor bioavailability and these problems are being addressed. Further improvements that will expand clinical applications of favonoids include mechanism-based precision medicine approaches which will identify critical mechanisms of action of individual favonoids with optimal activities that can be used in combination therapies. Keywords Cancer · Nuclear receptor · Nuclear translocation · Cell signaling · Apoptosis Introduction phenyl rings results in formation of favanones, favanols, favonols, favones, anthocyanidins and isofavones (Fig. 1). Flavonoids are polyphenolic phytochemicals produced in In addition, chalcones in which the ether ring of favonoids fruits, vegetables and grains and consumption of favonoid- has been cleaved are also considered to be members of the rich foods and nutriceuticals has been associated with a wide favonoid family of plant polyphenolics. Flavonoids are range of health benefts (rev. in [1–8]). Flavonoids contain a synthesized from phenylalanine and malonyl—Co A [9, common phenylchromen-4-one scafold which can be substi- 10] and over 8000 individual favonoids have been identi- tuted with a phenyl ring at C2 or C3 to give the favone and fed in plants [7]. Flavonoids are secondary metabolites that isofavone backbone structure. Further modifcations at C4 exhibit multiple functions in plants including their role in (a ketone group), C2–C3 (saturated or olefnic) plus hydroxy protecting against various internal and external stressors. or methoxy substituents on the phenylchromen-4-one and Consumption of fruits and vegetables has long been associ- ated with improved overall human health [11–14] and favo- noids have been recognized as one of the important classes * Stephen Safe [email protected] of phytochemicals that enhance health benefts. Moreover, there is evidence for widespread use of individual and fa- 1 Department of Veterinary Physiology and Pharmacology, vonoid mixtures as nutriceutical for maintaining health and Texas A&M University, 4466 TAMU, College Station, for treatment of multiple diseases and aliments. TX 77843-4466, USA 2 Department of Chemical Engineering, Texas A&M Efects of favonoids on non‑cancer and cancer University, College Station, TX 77843, USA endpoints in humans 3 Department of Nutrition, Texas A&M University, College Station, TX 77843, USA Flavonoids have been extensively investigated for their 4 Department of Biochemistry and Biophysics, Texas A&M efects on multiple non-cancer and cancer endpoints and University, College Station, TX 77843, USA Vol.:(0123456789)1 3 Toxicol Res. Fig. 1 Structure of favonoids and some individual members of each class PubMed lists over 123,000 publications dealing with these polyphenolics associated with individual flavonoid- phytochemicals. Although detailed structure–activity and induced responses are not well defned. Among the over mechanistic studies on favonoids are limited, the efects 123,000 citations on favonoids, there are many primary of these compounds have been attributed, in part to their and review articles on the health promoting efects of these activities as antioxidants, antimicrobial and antiviral compounds in several disease models of both prevention activities, radical trapping agents and as inhibitors of key and intervention/therapeutics. Results of laboratory and enzymes/factors such as cyclooxygenases, and acetylcho- preclinical studies would predict enormous health benefts linesterase. Many studies report that favonoids modulate from these compounds whereas human studies show mod- expression of multiple genes and gene products that result est and limited responses and some examples of efects in in benefcial efects however, the mechanisms and specifc humans that are associated with favonoid consumption 1 3 Toxicol Res. including aging and selected disease are summarized Diabetes below. Diabetes is another aging-related disease which in recent Aging and cardiovascular disease years has signifcantly increased in many countries due to diet-induced obesity. A recent meta-analysis of 18 diferent Biological aging is a complex process that results in the prospective cohort studies on polyphenol exposure and the temporal deterioration of cells due to the net accumulation risk of type 2 diabetes [23] reported that by comparison of of damage in multiple cell types and is due, in part, to age- extreme quintiles of intake there was an inverse association dependent decreases in cell repair and maintenance path- for favonoids, favonols, favan-3-ols, catechins, anthocya- ways, enhanced stress, DNA damage, mitochondrial injury nidins and isofavones. A similar inverse correlation was and infammation [15]. The major diseases where age is a observed for dietary intake of favonoids and the risk of ges- prominent risk factor include vascular disease and athero- tational diabetes mellitus [24]. A recent review summarized sclerosis, joint degeneration, metabolic diseases (obesity and past and current/ongoing clinical trials on efects of various diabetes), skin diseases, circulatory disease (hypertension, favonoids/polyphenols on diabetes and diabetic complica- coronary artery disease), eye diseases (macular degenera- tions including nephropathy, retinopathy, neuropathy and tion) and neurodegenerative diseases (Alzheimer’s, dementia cardiovascular complications [25]. Although there were and decreased cognitive-functions) [15]. The efects of favo- some indications of beneft, efects of the clinically approved noid or polyphenolic intake on mortality as an age-depend- and recommended use of favonoid mixtures for treatment of ent response has been investigated in several human studies diabetes and its complications were minimal despite encour- [16–22]. A recent report on the Danish Diet Cancer and aging results from animal models and cell culture studies Health Cohort [16] of 56,048 participants showed that die- [25, 26]. Nevertheless, meta-analysis of clinical trials (pri- tary intakes of approximately 500 mg/day of total favonoids marily with supplements) showed that favonols and isofa- decreased overall mortality and subsequent higher intakes of vones decreased body mass index, favonols also decreased up to 2000 mg/day did not further decrease mortality. The waist circumference whereas favonoids, favanones and authors also reported similar efects on decreased mortal- anthocyanins were not inversely associated with markers ity associated with dietary intakes of individual sub-classes of obesity [27]. Another report (single cohort) showed that of favonoids including favonols, favanols, favanones, other polyphenolics correlated with decreased body mass favones and anthocyanins. There was also evidence that index [28], however, favanols were not separated out in this dietary favonoids provide some mitigation of alcohol and study. Overall, the results suggest a possible role for favo- smoking-dependent higher rates of mortality. Interestingly noids in ameliorating the efects of diabetes and in diabetes there were some diferences in the mortality studies in the prevention but identifcation of specifc sub-classes of favo- various cohorts. For example, in the prospective Nurses’ noids that are most efcacious requires further investigation. Health Study II, a comparison between the lowest and high- est consumers of total favonoids was signifcant only in one Neurodegeneration model even though there was lower mortality rate in the high consumer group [22]. There was a signifcant increase in There are several studies showing that consumption of favo- mortality of women in the high vs. low grapefruit consum- noid and polyphenolic foods protects against some signs and ing group whereas selected favonoid/polyphenol-rich foods markers of neurodegeneration including various dementias such as red wine, tea, peppers, blueberries and strawberries and Alzheimer disease. Both intervention studies with vari- were associated with decreased mortality. The overall con- ous favonoid-enriched foods [29–33] and evidence from the sensus from most studies is that dietary favonoids signif- benefcial efects of the Mediterranean diet [34–37] suggest cantly lower mortality rates and can provide some protec- a role for these phytochemicals in neurodegenerative disease tion