目的 探讨新生霉素(novobiocin, NOVO)对肠黏膜辣椒素转运的调控作用。方法 体外Ussing chamber技术评价不同浓度NOVO刺激下辣椒素在不同肠黏膜透过量的差异。不同剂量NOVO对成年大鼠灌胃后测定各肠段瞬时受体电位香草酸亚型 1(transient receptor potential vanilloid 1, TRPV1)表达量。最后用LC-MS/MS技术检测NOVO对大鼠po辣椒素体内药动学参数的影响。结果 体外结果显示,5~50 μmol·L-1NOVO浓度依赖性地抑制辣椒素肠黏膜的透过,产生的抑制效果与TRPV1抑制剂钌红相当。体内结果示,NOVO预处理显著减少大鼠各肠段TRPV1的mRNA和蛋白表达。此外,NOVO降低po辣椒素的Cmax和AUC,但是对tmax无影响。然而,100~200 μmol·L-1 NOVO未表现出相似的作用,对肠黏膜透过率、肠段TRPV1表达和体内药动学参数无抑制作用。结论 NOVO可能通过抑制肠黏膜中TRPV1表达而减弱辣椒素经肠黏膜转运的能力,可能是1种新发现的TRPV1抑制剂。
Abstract
OBJECTIVE To explore the regulation of novobiocin(NOVO)on the intestinal transport of capsaicin. METHODS Ussing chamber was used to evaluate the influence of NOVO on the transport of capsaicin (CAP, a transient receptor potential vanilloid 1, substrate and agonist) in vitro. And the expression of TRPV1 in rat intestine was detected after oral administration of NOVO by qRT-PCR and Western blot. Finally, the effect of NOVO on the absorption of CAP in vivo was studied by LC-MS/MS. RESULTS In vitro data showed that there existed a dose-dependent relationship in the concentration range of 5-50 μmol·L-1,and even 5 μmol·L-1 NOVO could decrease the intestinal permeability of CAP across the intestine. Meanwhile, NOVO exhibited an inhibition level similar to that of ruthenium red (RR). In vivo data further demonstrated that NOVO down-regulated TRPV1 expression in the intestine in a concentration-dependent fashion. Meanwhile, oral co-administration of NOVO (12.5-100 mg·kg-1) decreased the Cmax and AUC of CAP in dosage-dependent ways, consistent with its role as a TRPV1 inhibitor, but it did not affect tmax. However, when the concentration of NOVO was higher than 50 μmol·L-1 in vitro or 100 mg·kg-1 in vivo, it may increase the permeability of CAP instead. CONCULUSION NOVO could be a potential TRPV1 inhibitor by attenuating the expression of TRPV1.
关键词
新生霉素 /
辣椒素 /
受体电位香草酸亚型1 /
肠黏膜
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Key words
novobiocin /
capsaicin /
TRPV1 /
intestine mucosa
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中图分类号：
R965
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脚注
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基金
国家自然科学基金项目资助(82003829);广州市科技计划项目资助(202102021103);广州市妇女儿童医疗中心院内科研培育基金资助(GWCMC2020-5-003)
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