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首页> 外文期刊>Biochemical Pharmacology >Coordinate regulation of UDP-glucuronosyltransferase UGT1A6 induction by 3-methylcholanthrene and multidrug resistance protein MRP2 expression by dexamethasone in primary rat hepatocytes.
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Coordinate regulation of UDP-glucuronosyltransferase UGT1A6 induction by 3-methylcholanthrene and multidrug resistance protein MRP2 expression by dexamethasone in primary rat hepatocytes.

机译：在原代大鼠肝细胞中通过3-甲基胆碱诱导的UDP-葡萄糖醛酸转移酶UGT1A6和地塞米松的多药耐药蛋白MRP2表达的协调调节。

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摘要

Concentration-dependent regulation of 3-methylcholanthrene (MC) inducibility of UDP-glucuronosyltransferase UGT1A6 by the synthetic glucocorticoid, dexamethasone (DEX) was studied. Treatment of cultured rat hepatocytes with MC, 0.1, 1, and 10 microM DEX, and MC combined with DEX, resulted in different induction patterns measured in the intact cells compared to that observed in the microsomes prepared from the same cells. DEX treatment in various concentrations caused a concentration-dependent increase in p-nitrophenol (p-NP) conjugation in intact cells (3-, 4-, and 5-fold over control, respectively), and it positively regulated MC induction (4-, 5-, and 6-fold over control, respectively). In contrast, DEX had smaller effect on microsomal p-NP conjugation (115, 200, 220% of control, respectively) and although MC induction was increased significantly by 0.1 microM DEX (520% of control), but higher concentrations of DEX (10 microM) decreased the degree of induction to 410%. Similar results obtained from in vivo experiments showed that at high DEX concentration (100mg/kg), the rate of MC induction (540%) decreased (420%). Permeabilization of the plasma membrane resulted in a 15-fold increase of p-NP conjugation indicating the importance of transport in the rate of overall p-NP elimination, and the induction pattern was similar to that observed in microsomes isolated from cells. Hyper-osmolarity (405 mOsmol/L) led to a 3-fold decrease of p-NP conjugation, the loss of DEX inducibility and reduction of the MRP2 protein level. Our results suggest coordinated regulation of UGT1A6 inducibility and substrate or product transport by DEX.
机译：研究了合成糖皮质激素地塞米松（DEX）对UDP-葡萄糖醛糖基转移酶UGT1A6的3-甲基胆碱（MC）诱导浓度的调节。用MC，0.1、1和10 microM DEX以及MC与DEX结合处理培养的大鼠肝细胞，与从相同细胞制备的微粒体中观察到的诱导模式不同，在完整细胞中测得的诱导模式不同。各种浓度的DEX处理导致完整细胞中对硝基苯酚（p-NP）共轭的浓度依赖性增加（分别是对照的3-倍，4-和5倍），并且它积极调节MC诱导（4- ，分别比对照高5倍和6倍）。相比之下，DEX对微粒体p-NP偶联的影响较小（分别为对照的115％，200％和220％），尽管MC诱导显着增加了0.1 microM DEX（为对照的520％），但DEX的浓度较高（10 microM）将诱导度降低到410％。从体内实验获得的类似结果表明，在高DEX浓度（100mg / kg）下，MC诱导率（540％）降低（420％）。质膜的透化作用导致p-NP共轭增加15倍，表明转运在整体p-NP消除速率中的重要性，并且诱导模式与从细胞中分离的微粒体中观察到的模式相似。高渗透压（405 mOsmol / L）导致p-NP共轭降低3倍，DEX诱导能力丧失和MRP2蛋白水平降低。我们的结果表明，通过DEX对UGT1A6的诱导性与底物或产物的转运进行协调调节。

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