血管加压素通过降低肝细胞牛磺鹅去氧胆酸盐含量来减轻牛磺鹅去氧胆酸盐诱导的肝毒性。

Vasopressin reduces taurochenodeoxycholate-induced hepatotoxicity by lowering the hepatocyte taurochenodeoxycholate content.

作者信息

Nakazawa T, Hoshino M, Hayakawa T, Tanaka A, Ohiwa T

机构信息

First Department of Internal Medicine, Nagoya City University Medical School, Japan.

出版信息

J Hepatol. 1996 Nov;25(5):739-47. doi: 10.1016/s0168-8278(96)80247-9.

DOI:10.1016/s0168-8278(96)80247-9

PMID:8938554

Abstract

BACKGROUND/AIMS: Vasopressin has been reported to reduce bile flow, but its effects on bile acid secretion and bile acid-related hepatotoxicity are still unclear. We therefore investigated the influence of vasopressin on the hepatotoxicity and biliary excretion of taurochenodeoxycholic acid in primary cultured rat hepatocytes and isolated perfused rat liver models.

METHODS/RESULTS: 1) Addition of vasopressin to hepatocyte cultures significantly decreased lactate dehydrogenase release as compared to cultures exposed to 1 mM taurochenodeoxycholic acid alone, and also reduced intracellular taurochenodeoxycholic acid content from 19.3 +/- 2.2 to 13.0 +/- 1.6 nmol/mg protein. After 30 min of preincubation with 1 mM taurochenodeoxycholic acid, rinsing and reculture of hepatocytes in bile acid-free medium resulted in gradual decrease in the intracellular level of the bile acid, and addition of vasopressin (10(-9) M) to the reculture medium accelerated this process. 2) Superimposition of vasopressin (330 pmol/l) for 10 min on taurochenodeoxycholic acid infusion (1.0 mumol/min: 25 mumol/l) caused a rapid increase in bile flow and biliary excretion of taurochenodeoxycholic acid (697 +/- 42 vs 584 +/- 27 nmol/10 min per g liver) from perfused rat livers, and significantly reduced lactate dehydrogenase release. 3) Superimposition of the PKC blocker H-7 (5 mumol/l) on taurochenodeoxycholic acid infusion (1.0 mumol/min: 25 mumol/l) caused a gradual increase in bile flow and biliary excretion of taurochenodeoxycholic acid. Furthermore, an additional infusion of vasopressin (100 pmol/l) for 10 min in the presence of H-7 produced a greater increase in bile flow and biliary excretion of taurochenodeoxycholic acid as compared with H-7 alone (754 +/- 71 vs. 657 +/- 26 nmol/g liver). 4) Continuous infusion of vasopressin (330 pmol/l) significantly increased the late peak (10-50 min) of horseradish peroxidase excretion from perfused livers (from 8.48 +/- 1.02 to 21.7 +/- 6.02 ng/g liver).

CONCLUSIONS

These findings suggest that vasopressin exerts a protective effect against taurochenodeoxycholic acid-induced hepatotoxicity by stimulating the secretion of this bile acid via intracellular vesicular transport systems.

摘要

背景/目的：有报道称血管加压素可减少胆汁流量，但其对胆汁酸分泌及胆汁酸相关肝毒性的影响仍不清楚。因此，我们在原代培养的大鼠肝细胞和离体灌注大鼠肝脏模型中研究了血管加压素对牛磺鹅去氧胆酸肝毒性和胆汁排泄的影响。

方法/结果：1）与仅暴露于1 mM牛磺鹅去氧胆酸的肝细胞培养物相比，向肝细胞培养物中添加血管加压素可显著降低乳酸脱氢酶释放，并将细胞内牛磺鹅去氧胆酸含量从19.3±2.2降至13.0±1.6 nmol/mg蛋白。用1 mM牛磺鹅去氧胆酸预孵育30分钟后，冲洗肝细胞并在无胆汁酸的培养基中重新培养，导致胆汁酸细胞内水平逐渐降低，向重新培养的培养基中添加血管加压素（10⁻⁹ M）加速了这一过程。2）在牛磺鹅去氧胆酸输注（1.0 μmol/min：25 μmol/l）过程中叠加血管加压素（330 pmol/l）10分钟，可使灌注大鼠肝脏的胆汁流量和牛磺鹅去氧胆酸的胆汁排泄迅速增加（697±42 vs 584±27 nmol/10分钟每克肝脏），并显著降低乳酸脱氢酶释放。3）在牛磺鹅去氧胆酸输注（1.0 μmol/min：25 μmol/l）过程中叠加PKC阻滞剂H-7（5 μmol/l）可使胆汁流量和牛磺鹅去氧胆酸的胆汁排泄逐渐增加。此外，在存在H-7的情况下额外输注血管加压素（100 pmol/l）10分钟，与单独使用H-7相比，可使胆汁流量和牛磺鹅去氧胆酸的胆汁排泄增加更多（754±71 vs. 657±26 nmol/g肝脏）。4）持续输注血管加压素（330 pmol/l）可显著增加灌注肝脏中辣根过氧化物酶排泄的晚期峰值（10 - 50分钟）（从8.48±1.02增至21.7±6.02 ng/g肝脏）。