The purpose of this review is to examine the effects of hesperidin and hesperetin on liver disorders. Metabolic dysfunction-associated steatotic liver disease is a complicated disorder influenced by many factors, including inflammation, diabetes and obesity. Currently, the most prominent treatment method is lifestyle changes. If left untreated, it can progress to cirrhosis, liver fibrosis and liver cancer. Hesperidin, which is a flavanone glycoside polyphenolic plant compound, belongs to the flavanone class and was first isolated from citrus peel. Hesperidin includes aglycone hesperetin and rutinoside sugar. It is the most dominant form of flavonoid in citrus fruits. In our review, we discuss the effects of these phytochemicals on liver diseases, focusing on their relationship with inflammation, blood sugar regulation and blood lipids. Hesperidin and hesperetin are seen as promising agents for many diseases. Their antioxidant and anti-inflammatory properties support this view. Although their low water solubility limits their potential effects, many studies have demonstrated their benefits. They are thought to play an effective role in inflammatory processes, particularly in liver diseases. More studies are required to find the optimum dosage and to use them as a therapeutic agent for the liver.

Although polyphenols inhibit glucose absorption and transport in vitro, it is uncertain whether this activity is sufficient to attenuate glycaemic response in vivo. We examined this using orange juice, which contains high levels of hesperidin. We first used a combination of in vitro assays to evaluate the potential effect of hesperidin and other orange juice components on intestinal sugar absorption and then tested whether this translated to an effect in healthy volunteers. Hesperidin attenuated transfer of 14C-labelled glucose across differentiated Caco-2/TC7 cell monolayers. The involvement of the sugar transporter GLUT2 was demonstrated by experiments carried out in the absence of Na to exclude the contribution of sodium-glucose linked transporter 1 and further explored by the use of Xenopus laevis oocytes expressing human GLUT2 or GLUT5. Fructose transport was also affected by hesperidin partly by inhibition of GLUT5, while hesperidin, even at high concentration, did not inhibit rat intestinal sucrase activity. We conducted three separate crossover interventions, each on ten healthy volunteers using orange juice with different amounts of added hesperidin and water. The biggest difference in postprandial blood glucose between orange juice and control, containing equivalent amounts of glucose, fructose, sucrose, citric acid and ascorbate, was when the juice was diluted (ΔCmax=–0·5 mm, P=0·0146). The effect was less pronounced when the juice was given at regular strength. Our data indicate that hesperidin can modulate postprandial glycaemic response of orange juice by partial inhibition of intestinal GLUT, but this depends on sugar and hesperidin concentrations.

The lack of robust measures of dietary exposure hinders a quantitative understanding of causal relationships between diet and health. Non-targeted metabolite fingerprinting was used to explore the relationships between citrus exposure in free-living human subjects, estimated by a FFQ, and the chemical content of urine. Volunteers (study 1, n 12; study 2, n 11) were classified into high-, medium- and low-frequency citrus consumption groups. Overnight and spot fasting urine samples were obtained after exposure to a standardised citrus-free evening meal. The urine samples were analysed by flow injection electrospray-ionisation MS followed by supervised multivariate data classification analysis to discover discriminatory features associated with the level of citrus exposure. Good separation of high and low citrus consumption classes was achieved. Deeper exploration of high-ranked explanatory mass signals revealed several correlated signals derived from proline betaine. Targeted analysis of the relative levels of proline betaine in both fasting and overnight urine samples demonstrated good correlation with FFQ exposure data. Acute exposure of volunteers to orange juice resulted in the appearance of proline betaine and several biotransformed products in postprandial urine samples. Biomarker validation showed sensitivities of 80·8–92·2 % and specificities of 74·2–94·1 % (false discovery rate-adjusted P values < 0·05) for elevated proline betaine in participants who reported high citrus consumption. Proline betaine biotransformation products displayed weaker quantitative relationships with habitual citrus exposure. Targeted screening for the presence of biotransformation products of hesperidin and narirutin, known to be abundant in oranges, revealed that they were relatively poor indicators of citrus exposure.

We have determined the absorption, conjugation and excretion of naringenin-7-O-rutinoside (narirutin) compared to the corresponding glucoside in an orange juice matrix in human subjects. Healthy volunteers (eight men and eight women), in a double blind, randomised, crossover study, consumed orange juice with (1) natural content of naringenin-7-O-rutinoside; (2) α-rhamnosidase-treated to yield naringenin-7-O-glucoside. Blood was sampled at twelve time points and three fractions of urine were collected over 24 h. The area under the plasma–time curve of naringenin from (2) α-rhamnosidase-treated orange juice was increased about 4-fold (P < 0·0001), peak plasma concentration (Cmax) was 5·4-fold higher (P < 0·0001) and Tmax was decreased from 311 to 92 min (P = 0·002) compared to untreated orange juice (1), indicating a change in absorption site from the colon to the small intestine. Furthermore, the amount in urine was increased from 7 to 47 % (P < 0·0001) of the dose after consumption of the α-rhamnosidase-treated orange juice (2). All urine samples contained both naringenin-7- and -4′-O-glucuronides. In addition, to examine the effect of dose and α-rhamnosidase treatment on hesperetin conjugate profiles, a further treatment where (3) orange juice fortified with three times the original content of hesperetin-7-O-rutinoside was used. Five hesperetin metabolites (3′-O-glucuronide; 7-O-glucuronide; 5,7-O-diglucuronide; 3′,7-O-diglucuronide; 3′-O-sulphate) were present after all treatments (1–3), with the same profile of the conjugates. The present data show that bioavailability of naringenin is increased by conversion from rutinoside to glucoside, but the profile of the conjugates of flavanones formed and excreted in urine is neither affected by the absorption site nor by a 3-fold change in dose.