title: Hepatic glucuronidation of resveratrol: interspecies comparison of enzyme kinetic profiles in human, mouse, rat, and dog.
abstract: The enzyme kinetic profiles of the formation of resveratrol-3-O-glucuronide (R3G) and resveratrol-4'-O-glucuronide (R4'G) by liver microsomes from humans, dogs, and rodents were investigated. Glucuronidation by human and dog liver microsomes to R3G and R4'G occurred for about 65% of applied resveratrol, and was significantly reduced to 10% when substrate concentration was increased 10-fold. In contrast, rodent microsomes glucuronidated about 90% of applied resveratrol independently of substrate concentration. Furthermore, in mouse and rat liver microsomes, resveratrol was almost exclusively conjugated at position 3, whereas human and dog livers also glucuronidated resveratrol at position 4' (ratio R3G:R4'G = 5:1). Interspecies differences were also found when calculating the enzyme kinetic profiles of both conjugates. Formation of R4'G in human and dog microsomes followed Michaelis-Menten kinetics, while R3G showed substrate inhibition at higher resveratrol concentrations. In mouse and rat microsomes, however, both R3G and R4'G formation exhibited auto-activation kinetics. Formation of R3G and R4'G by recombinant UGT1A1 also showed substrate inhibition kinetics that led to decreased intrinsic clearance values, while UGT1A9-catalyzed glucuronidation demonstrated substrate inhibition kinetics at position 3 and Hill kinetics for the formation of R4'G. In conclusion, resveratrol glucuronidation exhibited species-dependent differences, with the dog as the animal model that most closely represents humans in terms of this process.
authors.affiliation: Department of Clinical Pharmacy and Diagnostics, University of Vienna, Austria.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Maier-Salamon
authors.forename: Michaela
authors.initials: M
authors.lastname: Böhmdorfer
authors.forename: Theresia
authors.initials: T
authors.lastname: Thalhammer
authors.forename: Thomas
authors.initials: T
authors.lastname: Szekeres
authors.forename: Walter
authors.initials: W
authors.lastname: Jaeger
mesh_terms: D000818:Animals; D004285:Dogs; D004791:Enzyme Inhibitors / Q000378:metabolism*; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology* / Q000378:metabolism; D023421:Models, Animal; D008962:Models, Theoretical; D051381:Rats; D017208:Rats, Wistar; D000077185:Resveratrol; D013045:Species Specificity; D013267:Stilbenes / Q000378:metabolism*; D000099148:UGT1A1 Enzyme
chemical_list: D004791:Enzyme Inhibitors; D020719:Glucuronides; D014453:Glucuronosyltransferase; D007527:Isoenzymes; D000077185:Resveratrol; D013267:Stilbenes; D000099148:UGT1A1 Enzyme; C499731:resveratrol-4'-O-glucuronide