METHYLENE DIANILINE--A SELECTIVE BILE DUCT TOXICANT?
亚甲基二苯胺——一种选择性胆管毒物?
基本信息
- 批准号:2518658
- 负责人:
- 金额:$ 13.71万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1995
- 资助国家:美国
- 起止时间:1995-09-25 至 1999-08-31
- 项目状态:已结题
- 来源:
- 关键词:aniline bile ducts biotransformation cytotoxicity electron microscopy enzyme activity hepatotoxin high performance liquid chromatography laboratory rat liver cells liver function liver toxic disorder membrane potentials methane mitochondria morphology scintillation counter thin layer chromatography tight junctions toxicant interaction
项目摘要
DAPM (4,4'-diaminodiphenylmethane) is proposed as a selective bile duct
toxicant because DAPM causes morphological injury to biliary epithelial
cells (BEC) of the intrahepatic bile ducts without effects on hepatocytes
and rapidly impairs biliary functions, particularly glucose reabsorption
from the biliary traCt, but does not alter hepatocellular transport
functions. Little is known about the mechanisms by which DAPM and other
cholangiodestructive agents damage bile ducts. By 3 hr after DAPM, BEC
show ultrastructural alterations in mitochondria, loss of lumenal
microvilli and dilation of Golgi Cisternae. Studies of liver
mitochondria 3 hr after DAPM treatment demonstrate no alterations in
enzyme activities, mitochondrial permeability characteristics, or
histochemical staining patterns. The observation that BEC mitochondria
are an early site of DAPM injury may explain the rapidity and severity
of lesions caused by DAPM, and provides a unique opportunity to
investigate mechanisms of bile duct toxicants.
Our overall objective is to understand how and why DAPM causes early,
selective injury to bile duct cells. The focus of this application will
be on DAPM metabolites excreted in bile and their capacity to damage BEC.
Our experimental approach will use the 25 mg/kg dose of DAPM which causes
moderately injurious functional/structural alterations in BEC but does
not alter bile flow or damage hepatocytes. Studies of metabolite
excretion in bile and biliary function will be done in anesthetized rats
infused with taurocholate intraduodenally to maintain bile flow. AIM 1
will clarify the effects of DAPM on tight junction permeability using
paracellular markers and cytochemical ultrastructural methods. AIM 2
will characterize DAPM metabolites in vivo, particularly in bile, and
will use isolated cells to assess DAPM cytotoxicity in vitro in
hepatocytes versus BEC. AIM 3 will determine if inhibitors of
conjugation reactions decrease Phase Il enzymes in both BEC and
hepatocytes, identify possible proximate toxicants of DAPM by determining
extent of injury in rats whose biliary excretion of DAPM has been
modulated in vivo, and assess relative toxicities of suspect proximate
toxicants by in vitro cytotoxicity assays. Our new data provide such
strong evidence of the selective effect of DAPM on BEC, and particularly
on BEC mitochondria, that a new AIM 4 proposes physiological and
biochemical studies of mitochondrial function in isolated BEC treated
with DAPM.
The proposed research will contribute significantly to our understanding
of the mechanisms of BEC injury and provide a new model system to ask
questions about the role of BEC in bile formation.
DAPM(4,4 '-diaminodiphenylmethane)被提议作为选择性胆管
有毒,因为DAPM导致胆管上皮细胞形态学损伤
对肝细胞无影响的肝内胆管BEC
并迅速损害胆功能,特别是葡萄糖重吸收
但不改变肝细胞转运
功能协调发展的关于DAPM和其他药物的作用机制知之甚少。
胆管破坏剂损害胆管。DAPM后3小时,BEC
显示线粒体超微结构改变,
微绒毛和高尔基池扩张。肝脏研究
在DAPM处理后3小时,线粒体显示在
酶活性、线粒体通透性特征,或
组织化学染色模式。观察到BEC线粒体
是DAPM损伤的早期部位,可以解释DAPM损伤的快速性和严重性。
DAPM引起的病变,并提供了一个独特的机会,
研究胆管毒物的机制。
我们的总体目标是了解DAPM如何以及为什么会导致早期,
选择性损伤胆管细胞。该应用程序的重点将
对DAPM代谢产物在胆汁中的排泄及其对BEC的破坏能力有影响。
我们的实验方法将使用25 mg/kg剂量的DAPM,
BEC中中度损伤性功能/结构改变,但
不改变胆汁流量或损伤肝细胞。代谢物研究
将在麻醉大鼠中进行胆汁排泄和胆汁功能
尿道内注入牛磺胆酸盐以维持胆汁流动。要求1
将阐明DAPM对紧密连接渗透性的影响,
细胞旁标志物和细胞化学超微结构方法。目的2
将表征体内DAPM代谢物,特别是胆汁中的代谢物,
将使用分离的细胞在体外评估DAPM的细胞毒性,
肝细胞与BEC。AIM 3将确定是否抑制剂
缀合反应降低了BEC和BEC中的II相酶,
肝细胞,通过确定DAPM的可能近似毒物
在DAPM的胆汁排泄已被抑制的大鼠中的损伤程度
在体内调节,并评估可疑的近端
通过体外细胞毒性试验测定毒物。我们的新数据提供了这样的
强有力的证据表明,DAPM对BEC的选择性作用,特别是
在BEC线粒体上,一种新的AIM 4提出了生理和
BEC处理的分离的线粒体功能的生化研究
关于DAPM
拟议的研究将大大有助于我们了解
BEC损伤的机制,并提供了一个新的模型系统,
关于BEC在胆汁形成中的作用的问题。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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MARY F KANZ其他文献
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{{ truncateString('MARY F KANZ', 18)}}的其他基金
Biliary and Intestinal Cell Models of Drug Toxicity
药物毒性的胆道和肠细胞模型
- 批准号:
6730605 - 财政年份:2003
- 资助金额:
$ 13.71万 - 项目类别:
Biliary and Intestinal Cell Models of Drug Toxicity
药物毒性的胆道和肠细胞模型
- 批准号:
6651899 - 财政年份:2003
- 资助金额:
$ 13.71万 - 项目类别:
MITOCHONDRIAL FUNCTION--AGE, GENDER, AND DISEASE EFFECTS
线粒体功能——年龄、性别和疾病的影响
- 批准号:
2411404 - 财政年份:1997
- 资助金额:
$ 13.71万 - 项目类别:
METHYLENE DIANILINE--A SELECTIVE BILE DUCT TOXICANT?
亚甲基二苯胺——一种选择性胆管毒物?
- 批准号:
2155212 - 财政年份:1995
- 资助金额:
$ 13.71万 - 项目类别:
METHYLENE DIANILINE--A SELECTIVE BILE DUCT TOXICANT?
亚甲基二苯胺——一种选择性胆管毒物?
- 批准号:
2155211 - 财政年份:1995
- 资助金额:
$ 13.71万 - 项目类别:
MODULATION OF TOXIN INJURY BY HYPO/HYPER THYROIDISM
甲状腺功能减退/亢进对毒素损伤的调节
- 批准号:
3465124 - 财政年份:1987
- 资助金额:
$ 13.71万 - 项目类别:
MODULATION OF TOXIN INJURY BY HYPO/HYPER THYROIDISM
甲状腺功能减退/亢进对毒素损伤的调节
- 批准号:
3465126 - 财政年份:1987
- 资助金额:
$ 13.71万 - 项目类别:
MODULATION OF TOXIN INJURY BY HYPO/HYPER THYROIDISM
甲状腺功能减退/亢进对毒素损伤的调节
- 批准号:
3465125 - 财政年份:1987
- 资助金额:
$ 13.71万 - 项目类别:
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