Maier-Salamon Alexandra, Hagenauer Birgit, Wirth Michael, Gabor Franz, Szekeres Thomas, Jäger Walter
Department of Clinical Pharmacy and Diagnostics, University of Vienna, A-1090, Vienna, Austria.
Pharm Res. 2006 Sep;23(9):2107-15. doi: 10.1007/s11095-006-9060-z. Epub 2006 Aug 9.
The study's aim was to investigate the dose-dependent effect of sulfation and glucuronidation on intestinal absorption of resveratrol, a dietary constituent found in grapes and various medical plants.
The intestinal epithelial membrane transport kinetics and metabolism of resveratrol (10-200 microM) was studied using Caco-2 monolayers cultured in Transwells.
Along with resveratrol it was possible to identify three metabolites, namely, resveratrol-4'-O-glucuronide (M1), resveratrol 3-O-gucuronide (M2), and resveratrol-3-O-sulfate (M3) by LC/MS and NMR. Efflux of the glucuronides M1 and M2 followed Michaelis-Menten kinetics significantly favouring basolateral efflux. The predominant metabolite was the monosulfate M3, however, its formation was strongly inhibited at higher resveratrol concentrations. As biotransformation was either inhibited or saturated, total amount of resveratrol transported across the Caco-2 monolayers increased as much as 3.5-fold at 200 microM resveratrol. This value might be even higher when taking into account the high intracellular concentration of resveratrol, which accounted for up to 61% of the applied dose.
Our data demonstrate a concentration-dependent biotransformation of resveratrol in Caco-2 cells, which may also apply to human enterocytes affecting oral bioavailability.
本研究旨在探讨硫酸化和葡萄糖醛酸化对白藜芦醇肠道吸收的剂量依赖性影响，白藜芦醇是一种存在于葡萄和多种药用植物中的膳食成分。
使用在Transwells中培养的Caco-2单层细胞研究白藜芦醇（10 - 200微摩尔）的肠上皮细胞膜转运动力学和代谢。
通过液相色谱/质谱联用（LC/MS）和核磁共振（NMR），除白藜芦醇外，还鉴定出三种代谢产物，即白藜芦醇 - 4'-O - 葡萄糖醛酸苷（M1）、白藜芦醇3 - O - 葡萄糖醛酸苷（M2）和白藜芦醇 - 3 - O - 硫酸盐（M3）。葡萄糖醛酸苷M1和M2的外排遵循米氏动力学，显著有利于基底外侧外排。主要代谢产物是单硫酸盐M3，然而，在较高白藜芦醇浓度下其形成受到强烈抑制。由于生物转化要么被抑制要么饱和，在200微摩尔白藜芦醇时，跨Caco-2单层细胞转运的白藜芦醇总量增加了3.5倍。考虑到白藜芦醇在细胞内的高浓度（占给药剂量的61%），这个值可能更高。
我们的数据表明Caco-2细胞中白藜芦醇存在浓度依赖性生物转化，这也可能适用于影响口服生物利用度的人肠上皮细胞。
