DEHP-INDUCIBLE CYTOCHROME P450 FORMS IN KIDNEY AND LIVER
DEHP 诱导的细胞色素 P450 在肾脏和肝脏中的形式
基本信息
- 批准号:2153429
- 负责人:
- 金额:$ 15.37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1993
- 资助国家:美国
- 起止时间:1993-08-01 至 1998-04-30
- 项目状态:已结题
- 来源:
- 关键词:FK506 RNase protection assay calcium channel blockers cytochrome P450 diethylhexylphthalate drug adverse effect enzyme induction /repression fatty acid metabolism gene expression high performance liquid chromatography hydroxylation immunosuppressive kidney metabolism kidney pharmacology laboratory rabbit laboratory rat liver metabolism liver pharmacology membrane lipids northern blottings nuclear runoff assay peroxidation phospholipids scintillation counter western blottings
项目摘要
Members of the cytochrome P450 4A (CYP4A) subfamily catalyze the omega -
or penultimate -hydroxylation of saturated and unsaturated fatty acids and
prostaglandins. P450 4A forms are induced by peroxisome proliferators and
their induction represents one of the earliest cellular events following
exposure to these agents. It is thought that P450 4A induction and
formation of oxidized fatty acids may be essential for induction of
peroxisomal enzymes. There is considerable interest in the cellular
effects of peroxisome proliferators, because these chemicals have been
shown to cause hepatic tumors and testicular atrophy in rodents. In
addition, 4A forms synthesize products which mediate vasoconstriction of
renal vessels and an increase in P450-mediated fatty acid omega-
hydroxylase activity is reported prior to the elevation in blood pressure
in genetically-bred hypertensive rats. P450 4A forms have been identified
in many species and one human 4A form has been sequenced. In rats, three
members of the 4A family, 4A1, 4A2, and 4A3 have been identified and form
specific oligonucleotide probes and an antibody which recognizes the three
forms on western blots have been developed. Certain P450 4A forms exhibit
organ specific expression and are regulated by sex hormones. The
objectives of this competitive grant renewal are: 1) To localize specific
4A forms in distinct segments of the rat nephron by western blot analysis,
because there is considerable uncertainty over the identity of renal
forms. The localization of renal 4A forms will be compared in male and
female rats because expression of renal 4A forms is sex hormone-dependent;
2) To identify 4A forms which are induced by two immunosuppressive drugs,
cyclosporine and FK 506. Cyclosporine is an important therapeutic agent
used in transplantation surgery and in treatment of autoimmune diseases,
but nephrotoxicity is a major side effect. Studies indicate there is a
correlation between induction of fatty acid omega-hydroxylase activity by
cyclosporine and "the onset of nephrotoxicity; 3) To examine the
mechanisms by which calcium channel blockers suppress induction of hepatic
enzymes in DEHP (diethylhexyl phthalate), MEHP (monoethylhexyl phthalate)
or clofibrate treated rats or isolated hepatocytes and to examine whether
20-hydroxyeicosatetraenoic acid (20-HETE) and other omega- or penultimate-
oxidized fatty acids regulate intracellular calcium concentrations in
isolated rat hepatocytes; and 4) To examine the interferon-induced
suppression of hepatic 4A forms in phthalate or clofibrate treated rats or
isolated hepatocytes. Interferon has been shown to inhibit the induction
of P450 4A forms and its suppressive effects on peroxisome fatty acyl CoA
oxidase will be examined. The long-term goals of this proposal are to
determine the function of P450-mediated fatty acid omega-hydroxylases, its
role in peroxisome proliferation, and its physiological function in the
kidney.
细胞色素 P450 4A (CYP4A) 亚家族的成员催化 omega -
或饱和和不饱和脂肪酸的倒数第二个羟基化和
前列腺素。 P450 4A 形式由过氧化物酶体增殖剂诱导,
它们的诱导代表了以下最早的细胞事件之一
接触这些物质。据认为,P450 4A 感应和
氧化脂肪酸的形成对于诱导
过氧化物酶体酶。 人们对蜂窝技术非常感兴趣
过氧化物酶体增殖剂的影响,因为这些化学物质已被
显示会导致啮齿类动物的肝肿瘤和睾丸萎缩。在
此外,4A 形式合成介导血管收缩的产物
肾血管和 P450 介导的脂肪酸 omega- 增加
在血压升高之前报告羟化酶活性
在基因培育的高血压大鼠中。 P450 4A 形式已确定
在许多物种中,一种人类 4A 形式已被测序。在大鼠中,三
4A家族的成员4A1、4A2和4A3已被鉴定并形成
特定的寡核苷酸探针和识别这三个的抗体
已开发出蛋白质印迹形式。某些 P450 4A 表格展示
器官特异性表达并受性激素调节。这
此次竞争性赠款更新的目标是: 1) 本地化具体的
通过蛋白质印迹分析,4A 在大鼠肾单位的不同片段中形成,
因为肾脏的身份存在很大的不确定性
形式。将比较男性和女性肾 4A 形式的定位
雌性大鼠,因为肾 4A 形式的表达是性激素依赖性的;
2) 鉴定由两种免疫抑制药物诱导的4A形式,
环孢素和FK 506。环孢素是一种重要的治疗剂
用于移植手术和治疗自身免疫性疾病,
但肾毒性是主要副作用。研究表明有一个
诱导脂肪酸 omega-羟化酶活性之间的相关性
环孢素和“肾毒性的发生;3) 检查
钙通道阻滞剂抑制肝损伤的机制
DEHP(邻苯二甲酸二乙基己酯)、MEHP(邻苯二甲酸单乙基己酯)中的酶
或氯贝特治疗大鼠或分离的肝细胞,并检查是否
20-羟基二十碳四烯酸 (20-HETE) 和其他 omega- 或倒数第二-
氧化脂肪酸调节细胞内钙浓度
分离的大鼠肝细胞; 4) 检查干扰素诱导的
抑制邻苯二甲酸盐或安妥明治疗大鼠的肝脏 4A 形式,或
分离的肝细胞。干扰素已被证明可以抑制诱导
P450 4A 形式的形成及其对过氧化物酶体脂肪酰辅酶 A 的抑制作用
将检查氧化酶。该提案的长期目标是
确定 P450 介导的脂肪酸 omega-羟化酶的功能,其
过氧化物酶体增殖中的作用及其生理功能
肾。
项目成果
期刊论文数量(0)
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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Richard T. Okita其他文献
Richard T. Okita的其他文献
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{{ truncateString('Richard T. Okita', 18)}}的其他基金
DEHP-INDUCIBLE CYTOCHROME P450 FORMS IN KIDNEY AND LIVER
DEHP 诱导的细胞色素 P450 在肾脏和肝脏中的形式
- 批准号:
2153428 - 财政年份:1993
- 资助金额:
$ 15.37万 - 项目类别:
DEHP-INDUCIBLE CYTOCHROME P450 FORMS IN KIDNEY AND LIVER
DEHP 诱导的细胞色素 P450 在肾脏和肝脏中的形式
- 批准号:
2414948 - 财政年份:1993
- 资助金额:
$ 15.37万 - 项目类别:
DEHP-INDUCIBLE CYTOCHROME P450 FORMS IN KIDNEY AND LIVER
DEHP 诱导的细胞色素 P450 在肾脏和肝脏中的形式
- 批准号:
2153430 - 财政年份:1993
- 资助金额:
$ 15.37万 - 项目类别:
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