Bowles Sandra, Joubert Elizabeth, de Beer Dalene, Louw Johan, Brunschwig Christel, Njoroge Mathew, Lawrence Nina, Wiesner Lubbe, Chibale Kelly, Muller Christo
Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, Cape Town 7130, South Africa.
Plant Bioactives Group, Post-Harvest and Wine Technology Division, Agricultural Research Council, Infruitec-Nietvoorbij, Stellenbosch 7600, South Africa.
Molecules. 2017 Mar 30;22(4):554. doi: 10.3390/molecules22040554.
Insight into the mechanisms of intestinal transport and metabolism of aspalathin will provide important information for dose optimisation, in particular for studies using mouse models. Aspalathin transportation across the intestinal barrier (Caco-2 monolayer) tested at 1-150 µM had an apparent rate of permeability (P) typical of poorly absorbed compounds (1.73 × 10 cm/s). Major glucose transporters, sodium glucose linked transporter 1 (SGLT1) and glucose transporter 2 (GLUT2), and efflux protein (P-glycoprotein, PgP) (1.84 × 10 cm/s; efflux ratio: 1.1) were excluded as primary transporters, since the P of aspalathin was not affected by the presence of specific inhibitors. The P of aspalathin was also not affected by constituents of aspalathin-enriched rooibos extracts, but was affected by high glucose concentration (20.5 mM), which decreased the P value to 2.9 × 10 cm/s. Aspalathin metabolites (sulphated, glucuronidated and methylated) were found in mouse urine, but not in blood, following an oral dose of 50 mg/kg body weight of the pure compound. Sulphates were the predominant metabolites. These findings suggest that aspalathin is absorbed and metabolised in mice to mostly sulphate conjugates detected in urine. Mechanistically, we showed that aspalathin is not actively transported by the glucose transporters, but presumably passes the monolayer paracellularly.
深入了解阿萨伊拉辛的肠道转运和代谢机制将为剂量优化提供重要信息，特别是对于使用小鼠模型的研究。在1 - 150 μM浓度下测试阿萨伊拉辛跨肠道屏障（Caco - 2单层细胞）的表观渗透率（P），其表现出典型的吸收不良化合物的速率（1.73×10 cm/s）。主要的葡萄糖转运蛋白，即钠葡萄糖协同转运蛋白1（SGLT1）和葡萄糖转运蛋白2（GLUT2），以及外排蛋白（P - 糖蛋白，PgP）（1.84×10 cm/s；外排比率：1.1）被排除为主要转运蛋白，因为阿萨伊拉辛的P不受特定抑制剂存在的影响。阿萨伊拉辛的P也不受富含阿萨伊拉辛的路易波士提取物成分的影响，但受到高葡萄糖浓度（20.5 mM）的影响，这使P值降至2.9×10 cm/s。口服50 mg/kg体重的纯化合物后，在小鼠尿液中发现了阿萨伊拉辛代谢物（硫酸化、葡萄糖醛酸化和甲基化），但血液中未发现。硫酸盐是主要的代谢物。这些发现表明，阿萨伊拉辛在小鼠体内被吸收并代谢为尿液中检测到的主要硫酸盐共轭物。从机制上讲，我们表明阿萨伊拉辛不是由葡萄糖转运蛋白主动转运的，而是可能通过单层细胞旁细胞途径通过。
