Absorption, metabolism and excretion of flavanones from single portions of orange fruit and juice and effects of anthropometric variables and contraceptive pill use on flavanone excretion

Abstract

Oranges are rich sources of flavonoids that are bioactive and may protect against age-related diseases. The absorption of orange flavanones may be affected by factors such as processing and subject anthropometric variables, and the bioactivity of the absorbed phytochemicals depends on how they are metabolised during absorption. In a randomised cross-over study, twenty subjects consumed a single portion of orange fruit (150 g) or juice (300 g) that contained the flavanones narirutin and hesperidin, and an additional 109 subjects across a broad age range (18–80 years) consumed the juice. Flavanone metabolites were measured in regularly collected samples of plasma and urine. After consumption of fruit or juice, flavanone conjugates, but not the aglycones, were detected in plasma and urine. The flavanone conjugates were shown to include the 7- and 4′-O-monoglucuronides of naringenin, the 7- and 3′-O-monoglucuronides of hesperetin, two hesperetin diglucuronides and a hesperetin sulfo-glucuronide, but no aglycones or rutinosides. Analysis of the plasma pharmacokinetic and urinary excretion data on a dose-adjusted basis indicated no difference in absorption or excretion of either flavanone between the fruit and juice matrices. In the extended urinary excretion dataset the individual variation was very large (range 0–59 % urinary yield). There was a small but significant (P<0·05) decrease in the excretion of hesperetin (but not naringenin) with increasing age (P<0·05), but the effects of sex, BMI and contraceptive pill use were shown not to be associated with the variation in flavanone excretion.

Phase II Metabolism of Hesperetin by Individual UDP-Glucuronosyltransferases and Sulfotransferases and Rat and Human Tissue Samples

“…The authors argued that the kidney may be involved in postabsorption phase II metabolism, which could be explained by the expression of SULT1A1 in the kidneys (Meinl et al, 2006;Riches et al, 2009), the enzyme for which we found a high affinity toward hesperetin resulting in sulfonation at very low concentrations. In a third study in which human volunteers were given oranges or orange juice providing, respectively, 161 or 145 mg of hesperidin, hesperetin 7-O-glucuronide and 3Ј-Oglucuronide were detected in blood and plasma, as well as hesperetin 3Ј-O-sulfate, as qualified by liquid chromatographytandem mass spectrometry and metal complexation techniques (Brett et al, 2009). The absence of hesperetin 7-O-sulfate in these human volunteers is supported by the sulfonation kinetics found in the present study.…”

“…However, analysis of metabolites in plasma demonstrated the existence of other glucuronide and sulfo-conjugates as well (Matsumoto et al, 2004;Mullen et al, 2008;Brett et al, 2009). Different individual UGTs and SULTs probably possess different kinetics and regioselectivity for the conjugation of hesperetin, as has been reported for the glucuronidation and sulfonation of other flavonoids (Boersma et al, 2002;Otake et al, 2002;Zhang et al, 2007a;Tang et al, 2009), and, therefore, different levels of expression of UGTs and SULTs might lead to different metabolite patterns.…”

“…Enzymatic conversion of hesperidin before consumption to the monosaccharide hesperetin-7-O-glucoside has been demonstrated to result in absorption in the small intestine after deglucosylation by phloridzin hydrolase and/or facilitated transport into the intestinal cells by a sugar transporter such as sodium-glucose cotransporter 1 followed by intracellular deglucosylation (Nielsen et al, 2006). In the intestinal cells or during further first-pass metabolism, hesperetin aglycone is metabolized by UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs) into, respectively, glucuronidated and sulfonated metabolites, which have been detected in human and rat plasma (Manach et al, 2003;Matsumoto et al, 2004;Mullen et al, 2008;Brett et al, 2009). The intestinal barrier is believed to play a dominant role in phase II conjugation during the first-pass metabolism of hesperetin (Silberberg et al, 2006) and in its limited bioavailability because of efflux of the metabolites back to the intestinal lumen by ABC transport proteins Brand et al, 2008).…”

Microsomal Quercetin Glucuronidation in Rat Small Intestine Depends on Age and Segment

“…Wang et al (2006) found that rat intestinal microsomal CL int , V max , and K m values for glucuronidation of the isoflavones were unrelated to rates of glucuronidation in an intestinal perfusion model. Data from clinical trials of flavonoid metabolism using a wide range of ages are lacking, but interestingly, in a study of 129 subjects consuming orange juice, urinary excretion of hesperetin was decreased with advanced age, equating to a 4% decrease between the ages of 20 and 80 years (Brett et al, 2009). Although the mechanism of the decrease in urinary excretion remains to be explored, age could be considered as a potential, albeit weak, modifier of flavonoid metabolism.…”

Physiologically based kinetic modelling based prediction of oral systemic bioavailability of flavonoids, their metabolites, and their biological effects

“…Even though flavonoids have been intensively studied for decades [59], surprisingly there are only limited number of in vivo studies available that provide these data [12]. In most studies, flavonoid conjugates in plasma were identified and quantified from the amounts of aglycone liberated from conjugated metabolites by using β-glucuronidase and sulfatase to deconjugate the conjugated metabolites to their respective aglycone [60][61][62][63][64][65][66][67][68]. This method has been criticized for running a risk of underestimation and lack of information on the absolute structural conformation of flavonoid conjugates especially with respect to the conjugation position [60,61].…”