由P-糖蛋白介导的跨上皮长春碱分泌受到福斯高林衍生物的抑制。

Transepithelial vinblastine secretion mediated by P-glycoprotein is inhibited by forskolin derivatives.

作者信息

Hunter J, Hirst B H, Simmons N L

机构信息

Gastrointestinal Drug Delivery Research Centre, University of Newcastle upon Tyne, Medical School, UK.

出版信息

Biochem Biophys Res Commun. 1991 Dec 16;181(2):671-6. doi: 10.1016/0006-291x(91)91243-6.

DOI:10.1016/0006-291x(91)91243-6

PMID:1684494

Abstract

[3H]Vinblastine transport across MDCK (renal epithelial) cell layers has been characterised. The basal-to-apical [3H]vinblastine flux (JA-B) (at 10 nM) exceeded apical-to-basal flux by 19.6 fold. Net vinblastine secretion (JB-A - JA-B) was inhibited by verapamil (0.1 mM) primarily by a reduction in JB-A, consistent with net vinblastine secretion resulting from an inhibition of P-glycoprotein. 1,9-Dideoxy-forskolin and forskolin (0.1 mM) both resulted in significant inhibition of JB-A and net vinblastine secretion of 64.3 +/- 3.1% and 29.1 +/- 4.8% respectively. 7 beta-deactyl-7 beta-(gamma-N-methylpiperazino)-butyryl-forskolin was ineffective. Half-maximal inhibition of vinblastine secretion by 1,9-dideoxy-forskolin was observed at 65 microM. 1,9-dideoxy-forskolin is unable to stimulate adenylate cyclase, suggesting that this forskolin derivative is a potentially important lead antagonist of P-glycoprotein for circumvention of pleiotropic drug resistance.

摘要

已对[3H]长春碱跨MDCK（肾上皮）细胞层的转运进行了表征。在10 nM时，从基底到顶端的[3H]长春碱通量（JA - B）比从顶端到基底的通量高出19.6倍。维拉帕米（0.1 mM）抑制长春碱的净分泌（JB - A - JA - B），主要是通过降低JB - A，这与长春碱净分泌是由P - 糖蛋白抑制导致的一致。1,9 - 二脱氧福司可林和福司可林（0.1 mM）均导致JB - A和长春碱净分泌分别显著抑制64.3±3.1%和29.1±4.8%。7β - 去乙酰基 - 7β -（γ - N - 甲基哌嗪基） - 丁酰 - 福司可林无效。1,9 - 二脱氧福司可林在65 microM时观察到对长春碱分泌的半数最大抑制。1,9 - 二脱氧福司可林无法刺激腺苷酸环化酶，这表明这种福司可林衍生物是一种潜在重要的P - 糖蛋白拮抗剂，可用于规避多药耐药性。