Roger Clemens

Roger Clemens

Peter Pressman, MD

Citrus fruits, nearly 50 million metric tons of which were produced during the 2019–2020 season, contain an array of potential bioactive compounds in their peels, pulp, seeds, and juice. For more than 30 years, citrus-derived flavonoids have been studied for their potential health effects. Flavonoids are represented in six classes of compounds, namely flavones, flavonols, isoflavones, anthocyanidins, flavanones, and flavanols (Tripoli et al. 2007). The flavone moieties are present as either glycosides (typically a diglycoside) or aglycones (without the attached carbohydrate). Common flavanones (aglycone and glycoside forms) include naringenin, hesperetin, eriodictyol, and isosakuranetin, the concentrations of which vary based on citrus plant varieties and food preparation (Kahn et al. 2014) (Barreca et al. 2017). More than 350 aglycones and at least 100 glycosides of flavanones have been identified.

A brief overview of flavonoid absorption and post-absorptive metabolism indicates considerable heterogeneity in metabolism of flavonoids, and their potential physiological responses and mechanisms of action (Cassidy and Minihane 2017). In general, these substances, when consumed as glycosides and aglycones, are largely unabsorbed until reaching the colon. In this portion of the distal bowel, the indigenous microflora may hydrolyze and ferment flavonoids. If flavonoids are absorbed by the intestinal epithelium, they undergo phase I metabolism, the metabolites of which are transported to the liver for further metabolism (phase II), under the influence of at least 57 cytochrome genes and an array of enzyme isoforms of cytochrome P450 monooxygenases, and are subsequently excreted as polar substances or transported to target tissues where they may have biological effects. It is important to note that there is considerable heterogeneity in flavonoid metabolism, probably due to genetic variability, and there is marked individual urinary and fecal excretion unpredictability over 12 months.

It should be noted that following the ingestion of many of these flavonoids, they may alter the pharmacokinetics of medications. Naringenin in grapefruit juice and hesperidin in orange juice appear to increase the duration of plasma levels of drugs, such as atorvastatin and metformin, by reducing hepatic uptake transporters (Mandery et al. 2012). Yet there is evidence that a combination of hesperetin and naringenin may ameliorate airway inflammation and remodeling during a 4-week study using a murine model (Sevedrezazadeh et al. 2015). We should also remember that these flavonoids may exert off-target effects that impact insulin-modulating medications (e.g., metformin) and alter lipid metabolism. For example, among humans, the administration of hesperidin glycoside (500 mg/day) over 24 weeks yielded a marked improvement in plasma lipid profiles. The administration of hesperidin (800 mg/day) or naringin (500 mg/day) in capsule form produced inconsistent results in improving plasma lipid profiles, even among individuals who are mildly hypercholesterolemic (Miwa et al. 2005) (Demonty et al. 2010). These levels are equivalent to about 1.4 liters of orange juice, or 2.3 liters of mandarin orange juice. The interactions or dynamics of other flavonoids and their respective bioavailability in juices in these studies were obviated.

If flavonoids are absorbed by the intestinal epithelium, they undergo phase I metabolism, the metabolites of which are transported to the liver for further metabolism.

As plant-based dietary patterns are promoted through dietary guidelines and advocated by consumers, an analysis of 1999–2002 National Health and Nutrition Examination Survey data suggests the mean total flavonoid intake is about 200 mg/day. Interestingly, flavonoid intake from citrus fruit juices and citrus fruits was only about 6% of total intake, whereas tea represented nearly 84% based on 358 food codes (Chun et al. 2007).

The glycoside and aglycone forms of some flavanones, such as naringin and hesperidin (glycoside forms) and naringenin and hesperetin, their respective aglycones, have been the subject of considerable research for potential health-promoting effects (Zhao et al. 2020). For example, naringin and hesperidin may inhibit (reactive oxygen species) production and reduce the overexpression of proinflammatory modulators in macrophage cells and lung epithelial cells (Yang et al. 2012).

A recent review on neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, both of which primarily affect those over the age of 60, indicated doses of 3 mg/kg to about 50 mg/kg, depending on the compound administered to rats or mice over a short period, may reduce neuronal dysfunction induced in both acute and chronic experimental insults (Cirmi et al. 2016).

While the emerging evidence suggests there may be some health benefits associated with dietary citrus flavonoids, there remain an array of research challenges directed to future studies. As noted by Cassidy and Minihane (2017), there is a need for clinical trials to elucidate the relationship of flavonoid metabolism and specific organisms within the normal gut microbiome, the need to establish clinically relevant biomarkers of flavonoid intake and metabolic outcomes, and the need to investigate the impact of specific genotypes on flavonoid metabolism.

While recent studies suggest a role of citrus flavonoids in the management of dyslipidemia, insulin resistance, hepatic steatosis, obesity, and atherosclerosis, it is not clear how consistent or clinically significant that role may be; moreover, mechanisms of favorable outcomes are likely the result of multiple processes. Studies on dose, bioavailability, efficacy, and safety are required to propel the use of these putative therapeutic agents into the clinical arena. In the meantime, what can be said emphatically is that there are few things so delicious, refreshing, and colorful as citrus fruits. Regardless of health benefits, their balance of sweet and sour notes, water, acid, sugar, vitamins, and flavonoids make them a delightful and important part of the human diet.

About the Authors

Roger Clemens, DrPH, CFS
Contributing Editor, 2017–2018
Univ. of Southern California’s School of Pharmacy, Los Angeles, Calif.
clemens@usc.edu
Roger Clemens
Peter Pressman, MD
Director, The Daedalus Foundation
pdr@daedalushealth.com