Abstract
Previous rat toxicity studies of alpha-glycosyl isoquercitrin (AGIQ), a water-soluble flavonol glycoside derived from rutin, revealed systemic yellow bone discoloration. This investigative study was conducted to determine the AGIQ metabolite(s) responsible for the discoloration. Female Sprague–Dawley rats were administered dietary AGIQ at doses of 0%, 1.5%, 3.0%, or 5.0% (0, 1735.0, 3480.8, and 5873.7 mg/kg/day, respectively) for 14 days, followed by a 14- or 28-day recovery period. Measurements of quercetin in urine and quercetin, quercetin 3-O-glucuronide, kaempferol, and 3-o-methylquercetin metabolites of AGIQ in bone (femur), white and brown fat, and cerebrum samples were conducted following the exposure period and each recovery period. Gross examination of the femur revealed yellow discoloration that increased in intensity with dose and was still present in a dose-related manner following both recovery periods. Quercetin, at levels correlating with AGIQ dose, was measured in the urine following the 14-day exposure period and, at lower concentrations, 14 or 28 days following cessation of AGIQ exposure. All four metabolites were present in a dose-dependent manner in the femur following 14 days of dietary exposure; only quercetin, quercetin 3-O-glucuronide, and 3-o-methylquercetin were present during the recovery periods. Quercetin, quercetin 3-O-glucuronide, and 3-o-methylquercetin were detected in white fat (along with kaempferol), brown fat (excluding quercetin due to analytical interference), and cerebrum samples, indicating systemic availability of the metabolites. Collectively, these data implicate quercetin, quercetin 3-O-glucuronide, or 3-o-methylquercetin (or a combination thereof) as the most likely metabolite of AGIQ causing the yellow discoloration of bone in rats administered dietary AGIQ.
Highlights
In the recent 90-day rat toxicity study, the severity of bone discoloration was greater in female Sprague–Dawley rats than in males (Nyska et al 2016); female rats of the same strain were used as the test system in the current study
Abbreviated necropsies were performed on all animals following humane euthanasia at the end of the exposure period and 14- and 28-day recovery periods
Tissue samples collected at each necropsy were analyzed for the presence of four metabolites of alpha-glycosyl isoquercitrin (AGIQ) using a validated UPLC-MS/MS method at the David H
Summary
Division of Food Additives, National Institute of Health Sciences, 3‐25‐26 Tonomachi, Kawasaki‐ku, Kawasaki, Kanagawa 210‐9501, Japan and vegetables that have demonstrated potential benefits to human health, including reduction of inflammation, pain elimination, and cardiovascular protection (Amado et al 2009; Gasparotto Junior et al 2011; Kim et al 2010; Li et al 2011; Nyska et al 2016; Valentova et al 2014). These compounds, promoted as anti-oxidants, are available to consumers as dietary supplements. The U.S Food and Drug Administration (US FDA) granted a GRAS status for AGIQ (GRN 220) as an anti-oxidant (US FDA 2007)
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