Cis-resveratrol glucuronidation kinetics in human and recombinant UGT1A sources

Abstract

1. It was hypothesized that cis-resveratrol glucuronidation contributes to a greater extent to in-vitro disposition of total resveratrol than previously assumed. To this end, the kinetic data for cis-resveratrol glucuronidation are reported.

2. Glucuronidation assays were conducted in human liver and intestinal microsomes and in uridine diphosphate-glucuronosyltransferases (UGTs) UGT1A1, UGT1A6, UGT1A9, and UGT1A10. Kinetic parameters were estimated for the major cis-resveratrol-3-O-glucuronide (cis-R3G). Substrate inhibition was observed with apparent V_max, K_m and K_i of 6.1 ± 0.3/27.2 ± 1.2 nmol min⁻¹ mg⁻¹, 415 ± 48.1/989.9 ± 92.8 and 789.6 ± 76.3/1012 ± 55.9 μM in human intestinal microsomes (HIMs) and UGT1A6, respectively (estimate ± standard error (SE)). Biphasic kinetics were observed in human liver microsomes (HLMs), while sigmoidal kinetics were seen in UGT1A9 (V_max = 11.92 ± 0.2 nmol min⁻¹ mg⁻¹; K_m = 360 μM; n = 1.27 ± 0.07). The 4′-O-glucuronide (cis-R4′G) exhibited atypical kinetics in HLM, HIM, UGT1A1, and UGT1A10. UGT1A9 catalysed cis-R4′G formation at high substrate concentrations (V_max = 0.33 ± 0.015 nmol min⁻¹ mg⁻¹; K_m = 537.8 ± 67.8 μM).

3. In conclusion, although the rates of formation of cis-R3G in HLM and UGT1A9 were higher than those for trans-R3G, the contribution to total resveratrol disposition could not be determined fully due to atypical kinetics observed.

Keywords::

• Glucuronidation
• cis-resveratrol
• uridine diphosphate-glucuronosyltransferases (UGTs)
• atypical kinetics
• total resveratrol
• recombinant supersomes

Acknowledgements

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.