The Grapefruit Flavonoid Naringenin Inhibits Multiple Cardiac Ion Channels

Drinking fresh grapefruit juice is associated with a significant prolongation of the QT segment on the electrocardiogram (ECG) in healthy volunteers. Among the prominent flavonoids contained in citrus fruits, the flavanone naringenin is known to be a blocker of the human ether-a-go-go related gene (hERG) potassium channel. We hypothesized that naringenin could interfere with other major ion channels shaping the cardiac ventricular action potential (AP). To this end, we examined the effects of naringenin on the seven currents comprising the Comprehensive in vitro Pro-Arrhythmia (CiPA) panel for early arrhythmogenic risk assessment in drug discovery and development. We used automated patch-clamp of human ion channels heterologously expressed in mammalian cell lines to evaluate half-maximal inhibitory concentrations (IC50). Naringenin blocked all CiPA currents tested with IC50 values in the 30 µM – 100 µM concentration-range. The rank-order of channel sensitivity was the following: hERG > Kir2.1 > NaV1.5 late > NaV1.5 peak > KV7.1 > KV4.3 > CaV1.2. This multichannel inhibitory profile of naringenin suggests exercising caution when large amounts of grapefruit juice or other citrus juices enriched in this flavanone are drunk in conjunction with QT prolonging drugs or by carriers of congenital long QT syndromes.

Potential clinically significant drug interactions of drugs with fruit and berry juices

Any drug can potentially cause adverse drug reactions (ADRs), including serious and fatal. Some of them are caused by interactions with food, in particular, fruit and berry juices. Juices have a complex chemical composition and each of the chemicals can interact with drugs. Grapefruit juice is one of the most popular and well-studed in terms of potential drug interactions juices. Grapefruit juice is an inhibitor of CYP3A enzymes in the intestine involved in the presystemic metabolism of drug substrates. Therefore, it can increase their absorption. Apple juice at a concentration of 5% significantly reduces the activity of OATP, but not the activity of P-glycoprotein, which, for example, leads to a decrease in AUC and Cmax of fexofenadine to 30- 40% relative to the concentration of fexofenadine in patients drinking only water. Taking 200 ml of grape juice can reduce the concentration of phenacetin in blood plasma and increase the ratio of AUC of paracetamol to phenacetin due to the induction of CYP1A2 activity by grape juice flavonoids or by reducing the rate of absorption of phenacetin. To prevent ADRs, it is recommended to take drugs with water and and not consume simultaneously juices that are known to interact with drugs.

Bergamottin a CYP3A inhibitor found in grapefruit juice inhibits prostate cancer cell growth by downregulating androgen receptor signaling and promoting G0/G1 cell cycle block and apoptosis

Prostate cancer is the second leading cause of cancer related death in American men. Several therapies have been developed to treat advanced prostate cancer, but these therapies often have severe side effects. To improve the outcome with fewer side effects we focused on the furanocoumarin bergamottin, a natural product found in grapefruit juice and a potent CYP3A inhibitor. Our recent studies have shown that CYP3A5 inhibition can block androgen receptor (AR) signaling, critical for prostate cancer growth. We observed that bergamottin reduces prostate cancer (PC) cell growth by decreasing both total and nuclear AR (AR activation) reducing downstream AR signaling. Bergamottin’s role in reducing AR activation was confirmed by confocal microscopy studies and reduction in prostate specific antigen (PSA) levels, which is a marker for prostate cancer. Further studies revealed that bergamottin promotes cell cycle block and accumulates G0/G1 cells. The cell cycle block was accompanied with reduction in cyclin D, cyclin B, CDK4, P-cdc2 (Y15) and P-wee1 (S642). We also observed that bergamottin triggers apoptosis in prostate cancer cell lines as evident by TUNEL staining and PARP cleavage. Our data suggests that bergamottin may suppress prostate cancer growth, especially in African American (AA) patients carrying wild type CYP3A5 often presenting aggressive disease.

Analysis and Potential Value of Compounds Extracted From Star Ruby, Rio Red, and Ruby Red Grapefruit, and Grapefruit Juice Processing Residues via Steam Explosion

Culled whole grapefruit (WG) and grapefruit juice processing residues (GP) are currently incorporated into low-cost animal feed. If individual chemical components found within these side streams could be recovered as high-value coproducts, this would improve the overall value of the grapefruit crop. In this study, pectic hydrocolloids, sugars, volatiles, phenolics, and flavonoids were extracted from Star Ruby, Rio Red, and Ruby Red GP and WG using a continuous pilot scale steam explosion system. Up to 97% of grapefruit juice oils and peel oils could be volatilized and contained 87–94% d-limonene. The recovery of pectin, as determined by galacturonic acid content, was between 2.06 and 2.72 g 100 g−1. Of the phenolics and flavonoids analyzed in this study, narirutin and naringin were extracted in the amounts of up to 10,000 and 67,000 μg g−1, respectively.

Effect of grapefruit juice on CYP2E1 gene expression in obese and control rats

Background and Aims: The CYP2E1 gene encodes cytochrome P450 enzymes that play an essential role in liver fat metabolism. Additionally, grapefruit reduces plasma lipids in the body. Therefore, herbal medicines can be considered as an important treatment strategy. The present study aimed to evaluate the effect of grapefruit juice on CYP2E1 gene expression in obese and control rats. Materials and Methods: This experimental study was performed on 24 male Wistar rats weighing 180±20 g. Rats were divided into four groups: control (no treatment), high-fat diet group, treatment group 1 (high cholesterol diet with grapefruit juice 4 ml/kg), and treatment group 2 (high-fat diet with grapefruit juice) (8 ml/kg). They also gavaged for 6 weeks and CYP2E1 gene expression was finally determined. Statistical analyzes were performed using SPSS software (version 22). Results: The results of CYP2E1 gene expression indicated that grapefruit juice at a dose of 8 ml/kg can further reduce the expression of CYP2E1 gene in rats with fatty liver (1.09 ±0.038) than the dose of 4 ml/kg (1.27 ±0.24). This reduction in expression was statistically significant compared to that of the high-fat diet group (3.61 ±0.25) (P=0.003). Conclusion: The results of this study demonstrated that grapefruit juice reduces the expression of the CYP2E1 gene in obese rats due to naringin and recovers the disease by reducing the accumulation of triglycerides in the liver. Therefore, grapefruit juice can be considered as a therapeutic target in fatty liver disease and obesity.

Does Responsiveness to Basic Tastes Influence Preadolescents’ Food Liking? Investigating Taste Responsiveness Segment on Bitter-Sour-Sweet and Salty-Umami Model Food Samples

The objective of this study was to investigate the relationships between taste responsiveness and food liking in preadolescents. Model food samples of grapefruit juice (GF) and vegetable broth (VB) modified with four additions of sucrose and sodium chloride, respectively, were employed. Intensity perception for sweetness, sourness, and bitterness were measured in GF while saltiness and umami were measured in VB. The children (N = 148) also completed food choice, familiarity, stated liking and neophobia questionnaires. The test was conducted at school, with instructions provided remotely via video call. Four segments were defined differing in basic taste responsiveness. Segments and sucrose concentrations significantly affected liking for GF, while no significant effect of segments and sodium chloride concentrations occurred on liking for VB. An increasing sucrose concentration was positively associated with liking for GF only in the segment with low responsiveness to bitter and sour tastes. No significant differences across segments were found for food choice, familiarity, stated liking, and neophobia. Conclusively, relationships between taste responsiveness and liking are product and basic taste-dependent in addition to being subject-dependent. Strategies to improve acceptance by using sucrose as a suppressor for warning sensations of bitterness and sourness can be more or less effective depending on individual responsiveness to the basic tastes.

Growth of ‘Candidatus Liberibacter asiaticus’ in commercial grapefruit juice-based media formulations reveals common cell density-dependent transient behaviors

The phloem-restricted, insect-transmitted bacterium ‘Candidatus Liberibacter asiaticus’ (CLas) is associated with Huanglongbing (HLB), the most devastating disease of citrus worldwide. The inability to culture CLas impairs the understanding of its virulence mechanisms and the development of effective management strategies to control this incurable disease. Previously, our research group used commercial grapefruit juice (GJ) to prolong the viability of CLas in vitro. In the present study, GJ was amended with a wide range of compounds and incubated under different conditions to optimize CLas growth. Remarkably, results showed that CLas growth ratios were inversely proportional to the initial inoculum concentration. This correlation is likely regulated by a cell density-dependent mechanism, since diluting samples between subcultures allowed CLas to resume growth. Moreover, strategies to reduce the cell density of CLas, such as subculturing at short intervals and incubating samples under flow conditions, allowed this bacterium to multiply and reach maximum growth as fast as 3 days post inoculation, although no sustained exponential growth was observed under any tested condition. Unfortunately, cultures were only transient, since CLas lost viability over time; nevertheless, we obtained populations of 105 genome equivalents/ml repeatedly. Finally, we established an ex vivo system to grow CLas within periwinkle calli that could be used to propagate bacterial inoculum in the lab. In this study we determined the influence of a comprehensive set of conditions and compounds on CLas growth in culture. We hope our results will help guide future efforts towards the long-sought goal of culturing CLas axenically.