‘Insightful and comprehensive’: Grapefruit flavanones’ heart health benefits linked to gene expression changes

Multi-omics analysis of data from a double-blind, randomized, controlled, crossover trial with postmenopausal women revealed that six months of consuming grapefruit juice (GFJ) with 210 mg of naringenin glycosides led to 34 significant correlations between changes in gene expression and pulse wave velocity (PWV), considered a measure of arterial stiffness.

“This study showed for the first time that flavanone consumption in GFJ could induce changes in the gene expression profile of protein-coding genes but also of protein non-coding genes, microRNAs. These genes form a complex network of interactions that regulate cellular processes, particularly those involved in inflammation, cell adhesion and cell mobility,” ​wrote scientists from the University of Belgrade (Serbia) and the Université Clermont Auvergne (France) in Frontiers in Nutrition​.

“Therefore, the results of this study suggest that regular consumption of flavanone in grapefruit juice could modulate the expression of genes that could contribute to the prevention of vascular dysfunction and, consequently, the development of CVD.”​

The study was funded by the Florida Department of Citrus, and the juice was provided by Ocean Spray.

“An insightful and comprehensive study” ​

Commenting independently, Mark Miller, PhD, principal at Kaiviti Consulting, LLC, called the study “insightful and comprehensive”.  ​

“Interventions that focus on altering how we use our genetic tool kits have far reaching health potential,” ​Dr Miller told NutraIngredients-USA. “In this case there were myriad of benefits to consuming grapefruit juice on immunity and inflammation, signal transduction, cell adhesion and motility, vascular form & function (stiffness, hypertension) and metabolic pathways.​

“Some of the unique features of this comprehensive bioinformatics study define a myriad of mechanisms of action including: (1) altered gene expression (2) docking of naringenin (and metabolites) to the key transcription factors NF-kB and STAT-3 (3) activity of inhibitory mRNA (miRNA) (4) how white blood cells stick to the vasculature and migrate into blood vessels (5) immunity e.g., antigen presentation, and (6) how cells communicate and make decisions.”​

But there was one specific interaction that Dr Miller found especially fascinating, and that was the action of DDAH1, an enzyme that lowers the blood levels of methyl-arginines.

“These arginine analogues compete with L-arginine to make nitric oxide from the endothelium,” ​he explained. “The authors noted that arterial stiffness, as measured by pulse waver velocity, was negatively correlated with the expression of DDAH.​

“The ability of grapefruit juice isoflavones to correct this imbalance is not to be understated. It is another key action supporting the well-established concept that I posed in 1987​ that hypertension was caused by a compromised ability of the endothelium to release a vasodilator we now know as nitric oxide,” ​said Dr Miller.

Study details​

The new study used data from an earlier randomized control trial​ with 48 postmenopausal women randomly assigned to consume either a flavanone-free control juice or a flavanone-rich grapefruit juice for six months.

The data was subject to multi-omics analysis and revealed that the flavanone-rich juice led to significant changes in a range of measures, as highlighted already by Dr Miller.

“[T]his human study based on microarray analysis showed that chronic consumption of GFJ naturally rich in flavanones for 6 months induced changes in the expression of protein-coding genes and miRNAs in postmenopausal women’s PBMCs [Peripheral Blood Mononuclear Cell],” ​said the researchers.

“The observed differentially expressed genes by GFJ flavanones are involved in biological processes that include inflammation, immune responses, cell motility, vascular-related functions and signal transduction and are important for vascular homeostasis. ​

“The obtained results also agree with the capacity of grapefruit flavanones to protect from arterial stiffness, as we have reported previously in the same study population.”​

One final thought…​

Dr Miller shared one additional comment with NutraIngredients-USA: “Grapefruit juice and grapefruit flavones have gotten a bad rap in the biomedical community as they are metabolized by CYP3A4, which is also the pathway that metabolizes statins,” ​he said. “From that perspective, grapefruit isoflavones may raise the effective concentration of statins and, as a result, patients are told to avoid grapefruit juice. A concept where pharma fails to adjust and seeks to protect itself. ​

“The irony here is that when physicians adjust the dose of statins, to achieve the desired goal, they follow semi-log dose escalation (3, 10, 30, 100 etc.) which are far greater jumps than could be achieved by consuming grapefruit flavones. ​

“When considering the comprehensive actions of grapefruit flavones on cardiovascular health and inflammation vs. the actions and complications of statins, I say hand me a grapefruit juice please.”​

Source: Frontiers in Nutrition​
Published online, doi: 10.3389/fnut.2022.907595​
“Grapefruit Juice Flavanones Modulate the Expression of Genes Regulating Inflammation, Cell Interactions and Vascular Function in Peripheral Blood Mononuclear Cells of Postmenopausal Women”​
Authors: I. Krga et al.