Distribution of trans‐resveratrol and its metabolites after acute or sustained administration in mouse heart, brain, and liver

Abstract

Scope Trans‐resveratrol is widely studied for its potentially beneficial effects on numerous disorders. It is rapidly metabolized and its metabolites can exhibit biological activity. The present study aimed to investigate whether acute or sustained trans‐resveratrol administration impacted on the distribution of trans‐resveratrol and its metabolites in brain, heart, and liver. Methods and results We used ultra‐HPLC quadrupole‐TOF (UHPLC‐Q‐TOF) in a full‐scan mode to identify and assess large numbers of resveratrol metabolites. For acute intake, mice were overfed with a single dose of trans‐resveratrol (150 mg/kg) and organs were collected after 30 and 60 min. For sustained intake, trans‐resveratrol was given in the chow (0.04% w/w corresponding to 40 mg/kg/day), and plasma and the organs were collected after 3 months of this resveratrol diet. We found that trans‐resveratrol‐3‐O‐glucuronide and resveratrol‐3‐sulfate were the main metabolites found after acute intake, and free trans‐resveratrol (in the brain and heart) and dihydroresveratrol derivatives were found after sustained administration Conclusions Our results show notable differences between acute and sustained administration of trans‐resveratrol and distribution of trans‐resveratrol and its metabolites in mouse heart, brain, and liver. The results suggest a strategy for development of galenic forms of resveratrol.

Endothelial Cells Deconjugate Resveratrol Metabolites to Free Resveratrol: A Possible Role in Tissue Factor Modulation

“…An additional novel finding of the present study is that RV conjugation to RVmet was also observed in endothelial cells, mainly to the sulfated metabolite RV3S. Consistent with these findings, the sulfated forms of RV predominate over the glucuronidated conjugates in human plasma and urine, specifically RV3S, while mouse metabolism favors the glucuronidated forms . However, little is known about the predominant metabolites that accumulate in target human tissues, particularly in endothelial cells.…”

“…Moreover, Menet et al reported differences in RV and RVmet tissue accumulation in mice after an acute and sustained intake of RV . A single dose of RV resulted in RVmet accumulation in the mouse heart and brain, whereas the sustained intake of RV favored the accumulation of free RV in these tissues, supporting the saturation of the RV metabolic enzymes in tissues.…”

“…In the present study, the properties of the rapidly metabolized forms of RV, such as RV glucuronide and sulfate metabolites, were examined to address this issue. For this purpose, the main physiological RVmet (RV3G, RV4G, and RV3S) were selected. Any of the RVmet tested modulated the TF activity, protein levels, or gene expression at any of the doses tested.…”

“…Although approximately 75% of RV is absorbed in humans after oral consumption, the presence of free RV in plasma as a circulating metabolite is low as a consequence of its rapid and extensive phase‐II metabolism by the liver, intestinal tract, and gut microbiota . Consequently, ≈20 RV metabolites (RVmet) have been identified in human and animal plasma, urine, and some tissue samples, in particular the sulfated and the glucuronidated forms RV‐3‐ O ‐β‐ d ‐glucuronide (RV3G), RV‐4′‐ O ‐ d ‐glucuronide (RV4G), and RV‐3‐ O ‐sulfate (RV3S) (Figure S1C–E, Supporting Information). On the other hand, piceid is deglycosylated to RV by a glycosidase enzyme before being absorbed in the intestine and undergoing phase‐II metabolism to generate RVmet .…”

Resveratrol in Cancer Patients: From Bench to Bedside

“…Moreover, trans-resveratrol and relative conjugates were found to be distributed mainly in the liver and kidneys, the primary sites of metabolism and excretion, but radioactivity of 14 C-labeled resveratrol was observed also in the oral cavity, stomach and intestines suggesting a "resveratrol reservoir" of these tissues [14,20]. In accordance with previous investigations, Menet et al confirmed, in an animal model, that after both single dose and sustained resveratrol intake, the distribution was higher in kidneys and the liver, whereas recently the pharmacokinetic analysis by Su and colleagues demonstrated that the major distribution of resveratrol, derivatives and metabolites occurred in the gastrointestinal tract after oral intake [21,22]. As mentioned above, resveratrol undergoes rapid and extensive metabolism, and several studies were conducted in order to identify resveratrol metabolites.…”