UCIBIO/REQUIMTE, Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.
Instituto de Investigaciones Farmacológicas (ININFA), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, CONICET, Buenos Aires, Argentina.
Toxicol Appl Pharmacol. 2020 Jan 1;386:114832. doi: 10.1016/j.taap.2019.114832. Epub 2019 Nov 19.
In vitro studies showed that 1-(propan-2-ylamino)-4-propoxy-9H-thioxanthen-9-one (TX5) increases P-glycoprotein (P-gp) expression and activity in Caco-2 cells, preventing xenobiotic toxicity. The present study aimed at investigating TX5 effects on P-gp expression/activity using Wistar Han rats: a) in vivo, evaluating intestinal P-gp activity; b) ex vivo, evaluating P-gp expression in ileum brush border membranes (BBM) and P-gp activity in everted intestinal sacs; c) ex vivo, evaluating P-gp activity in everted intestinal sacs of the distal and proximal ileum. TX5 (30 mg/kg, b.w.), gavage, activated P-gp in vivo, given the significant decrease in the AUC of digoxin (0.25 mg/kg, b.w.). The efflux of rhodamine 123 (300 μM), a P-gp fluorescent substrate, significantly increased in TX5-treated everted sacs from the distal portion of the rat ileum, when P-gp activity was evaluated in the presence of TX5 (20 μM), an effect abolished by the P-gp inhibitor verapamil (100 μM). No increases on P-gp expression or activity were found in TX5-treated BBM of the distal ileum and everted distal sacs, respectively, 24 h after TX5 (10 mg/kg, b.w.) administration. In vivo, no differences were found on digoxin portal concentration between control (digoxin 0.025 mg/kg, b.w., intraduodenal) and TX5-treated (digoxin+TX5 20 μM, intraduodenal) rats. The observed discrepancies in digoxin results can be related to differences in TX5 dose administered and used methodologies. Thus, the results show that TX5 activates P-gp at the distal portion of the rat ileum, and, at the higher dose tested (30 mg/kg, b.w.), seems to modulate in vivo the AUC of P-gp substrates.
体外研究表明，1-(异丙基氨基)-4-丙氧基-9H-噻吨-9-酮（TX5）可增加 Caco-2 细胞中的 P-糖蛋白（P-gp）表达和活性，从而防止外源性毒物毒性。本研究旨在使用 Wistar Han 大鼠研究 TX5 对 P-gp 表达/活性的影响：a）体内，评估肠道 P-gp 活性；b）离体，评估回肠刷状缘膜（BBM）中的 P-gp 表达和外翻肠囊中的 P-gp 活性；c）离体，评估回肠远段和近段外翻肠囊中的 P-gp 活性。TX5（30 mg/kg，bw）灌胃，体内激活 P-gp，因为地高辛（0.25 mg/kg，bw）的 AUC 显著降低。当用 TX5（20 μM）评估 P-gp 活性时，P-gp 荧光底物罗丹明 123（300 μM）的外排显著增加 TX5 处理的大鼠回肠远段外翻囊中，该作用被 P-gp 抑制剂维拉帕米（100 μM）消除。在 TX5（10 mg/kg，bw）给药 24 小时后，TX5 处理的远段回肠 BBM 和外翻远段囊中的 P-gp 表达或活性均无增加。体内，在对照（地高辛 0.025 mg/kg，十二指肠内）和 TX5 处理（地高辛+TX5 20 μM，十二指肠内）大鼠之间，门静脉地高辛浓度没有差异。地高辛结果的观察差异可能与 TX5 给药剂量和所用方法的差异有关。因此，结果表明 TX5 在大鼠回肠远段激活 P-gp，并且在测试的较高剂量（30 mg/kg，bw）下，似乎调节 P-gp 底物的 AUC 。
