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ORGANIC ANION TRANSPORT AT THE BILE CANALICULUS

胆管内的有机阴离子转运

基本信息

批准号：
3250269
负责人：
LAWRENCE R CURTIS
金额：
$ 7.48万
依托单位：
OREGON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1982
资助国家：
美国
起止时间：
1982-09-10 至 1987-08-31
项目状态：
已结题

项目摘要

The organochlorine insecticide analogs mirex and chlordecone impair biliary excretion of readily excretable organic anions in rats (i.e., polar metabolites of PCB's and imipramine, phenolphthalein glucuronide, and exogenous taurocholate). Hepatobiliary dysfunction is not associated with marked cholestasis or hepatocellular necrosis but diminished capacity to concentrate organic anions in bile. Inhibition ATPase activities in various subcellular fractions by these agents (particularly the Na+, K+- and oligomycin-insensitive Mg2+-ATPase (OIMATPase) of liver plasma membranes) indicates energy transduction as a site of toxicity. Na+, K+-ATPase provides energy for Na+-coupled uptake of bile salts from the circulation into the liver and is probably a "pump" responsible for electrolyte and accompanying water movement into bile. The role of the OIMATPase present in high activity in bile canaliculi enriched fractions (BCEF) is not understood. A major objective of this research is to determine whether inhibition of BCEF OIMATPase is a primary event in mirex and chlordecone-induced hepatobiliary dysfunction and development of a mechanistic model for this toxicity. Definition of the role of this enzyme in biliary excretion and the bile formation process per se is an integral part of this goal. The working hypothesis is that BCEF OIMATPase activity represents a H+-ATPase which provides energy for canalicular transport of organic solutes and/or a "myosin-like" ATPase which plays a role in contraction of bile canaliculi and maintenance of "tone" in the biliary tree. The above general objective will be approached by physiological and biochemical methods. The potential roles of hepatic blood flow and oxygenation, bile salt composition and concentration, and plasma membrane lipid composition in mirex- and chlordecone-induced hepatobiliary dysfunction will be evaluated. Intact rat studies will examine the sequence of impaired organic anion biliary excretion, inhibition of BCEF OIMATPase, and increased permeability of the biliary tree in both time course and pharmacological reversal experiments. Vesicular transport studies in BCEF aimed at determining the role of OIMATPase in coupled transport of organic anions are ongoing. Studies aimed at determining the site and mechanism of organochlorine action at the biomembrane level (BCEF) are proposed. These will involve the effects of mirex and chlordecone on BCEF physical properties as determined in differential scanning calorimetry and spin labeling (ESR) studies.

有机氯杀虫剂类似物灭螨和十氯酮对胆道有害

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Biliary excretion of [14C]taurocholate by rainbow trout (Salmo gairdneri) is stimulated at warmer acclimation temperature.

虹鳟鱼（Salmo gairdneri）在较高的驯化温度下会刺激胆汁排泄[14C]牛磺胆酸盐。

DOI：
10.1016/0742-8413(86)90170-2
发表时间：
1986
期刊：
Comparative biochemistry and physiology. C, Comparative pharmacology and toxicology
影响因子：
0
作者：
Curtis,LR;Kemp,CJ;Svec,AV
通讯作者：
Svec,AV

Impaired biliary excretion of taurocholate associated with increased biliary tree permeability in mirex- or chlordecone-pretreated rats.

在灭蚁灵或十氯酮预处理的大鼠中，牛磺胆酸盐的胆汁排泄受损与胆道树通透性增加相关。