title: Differential effects of two citrus flavanones on bone quality in senescent male rats in relation to their bioavailability and metabolism.
abstract: The effect of hesperidin (Hp) and naringin (Nar), two major citrus flavanones, on the regulation of bone metabolism was examined in male senescent rats. Twenty -month -old gonad-intact male Wistar rats received a casein-based diet supplemented with or without either 0.5% hesperidin (Hp), 0.5% naringin (Nar) or a mix of both flavanones (Hp+Nar, 0.25% each). After 3 months, daily Hp intake significantly improved femoral bone integrity as reflected by improvements in total and regional bone mineral densities (BMD) (9.7%-12.3% improvements, p<0.05) and trabecular bone volume fraction (24.3% improvement, p<0.05) at the femur compared with control group. In contrast, naringin exerted site-specific effects on BMD (10.2% improvement at the distal metaphyseal area, p<0.05) and no further benefit to bone mass was observed with the mix of flavanones. Bone resorption (DPD) was significantly attenuated by Hp and Nar given alone (40.3% and 26.8% lower compared to control, p<0.05, respectively) but not by the mixture of the two. All treatments significantly reduced expression of inflammatory markers to a similar extent (IL-6, 81.0-87.9% reduction; NO, 34.7-39.5% reduction) compared to control. Bone formation did not appear to be strongly affected by any of the treatments (no effect on osteocalcin levels, modest modulation of tibial BMP-2 mRNA). However, as previously reported, plasma lipid-lowering effects were observed with Hp and Nar alone (34.1%-45.1% lower for total cholesterol and triglycerides compared to control, p<0.05) or together (46% lower for triglycerides, p<0.05). Surprisingly the plasma circulating level of naringin (8.15μM) was >5-fold higher than that of hesperidin (1.44μM) at equivalent doses (0.5%) and a linear reduction in plasma levels was observed upon co-administration (0.25% each) indicating absence of competition for their intestinal absorption sites and metabolism. The higher efficacy of Hp at a lower plasma concentration than naringin, as well as the identification of the major circulating metabolite of hesperidin (hesperetin-7-O-glucuronide) underlines the importance of flavanone bioavailability and metabolism in their biological efficacy and suggests a structure-function relationship in the mechanism of action of the active metabolites.
authors.affiliation: INRA Clermont/Theix, Human Nutrition Unit UMR1019, St. Genès Champanelle, F-63122, France. habauzit@clermont.inra.fr
authors.forename: Véronique
authors.initials: V
authors.lastname: Habauzit
authors.forename: Sandra Maria
authors.initials: SM
authors.lastname: Sacco
authors.forename: Angel
authors.initials: A
authors.lastname: Gil-Izquierdo
authors.forename: Anna
authors.initials: A
authors.lastname: Trzeciakiewicz
authors.forename: Christine
authors.initials: C
authors.lastname: Morand
authors.forename: Denis
authors.initials: D
authors.lastname: Barron
authors.forename: Stéphane
authors.initials: S
authors.lastname: Pinaud
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Offord
authors.forename: Marie-Noëlle
authors.initials: MN
authors.lastname: Horcajada
mesh_terms: D000375:Aging; D000818:Animals; D001483:Base Sequence; D001835:Body Weight / Q000187:drug effects; D015519:Bone Density; D001842:Bone and Bones / Q000187:drug effects*; D002957:Citrus / Q000737:chemistry*; D017931:DNA Primers; D044950:Flavanones / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry
chemical_list: D017931:DNA Primers; D044950:Flavanones