Differential effects of two citrus flavanones on bone quality in senescent male rats in relation to their bioavailability and metabolism

• Published in: Bone (New York, N.Y.) N.Y.), 2011-11, Vol.49 (5), p.1108-1116
• Main Authors: Habauzit, Véronique, Sacco, Sandra Maria, Gil-Izquierdo, Angel, Trzeciakiewicz, Anna, Morand, Christine, Barron, Denis, Pinaud, Stéphane, Offord, Elisabeth, Horcajada, Marie-Noëlle
• Format: Article
• Language: English
• Subjects: Aging; Animals; Base Sequence; Biological and medical sciences; Body Weight - drug effects; Bone and Bones - drug effects; Bone Density; Citrus; Citrus - chemistry; DNA Primers; Flavanones - pharmacokinetics; Flavanones - pharmacology; Fundamental and applied biological sciences. Psychology; Life Sciences; Male; Organ Size - drug effects; Orthopedics; Rats; Rats, Wistar; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Vertebrates: anatomy and physiology, studies on body, several organs or systems
• ISSN: 8756-3282; 1873-2763; 8756-3282
• DOI: 10.1016/j.bone.2011.07.030

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 (8.15 μM) was > 5-fold higher than that of hesperidin (1.44 μM) 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.