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TOXICOLOGY OF PERFLUORINATED FATTY ACID-LIPID CONJUGATES

全氟化脂肪酸-脂质缀合物的毒理学

基本信息

批准号：
2180716
负责人：
RICHARD Eugene PETERSON
金额：
$ 19.13万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
1989
资助国家：
美国
起止时间：
1989-06-01 至 1994-11-30
项目状态：
已结题

项目摘要

Perfluorinated fatty acids, represented by perfluorooctanoic acid (PFOA) and perfluorodecanoic acid (PFDA), are a new class of peroxisome proliferators. Like other classes (hypolipidemic drugs and phthalate esters) they produce a marked pleiotropic response in rodent liver. No information exists on the metabolic fate of PFOA or PFDA, their effects on hepatic fatty acid oxidation, or mechanisms by which they perturb normal lipid metabolism. In rats PFDA is more biologically potent than PFOA, but the cause is unknown. The hepatocarcinogenic potential of these agents is also not known. Perfluorinated fatty acids are potentially important chemicals to study because they (1) have widespread commercial usage, (2) are a new class of peroxisome proliferators that might not be hepatocarcinogenic, (3) might serve as probes for studying normal lipid metabolism, and (4) might be useful prototypes for studying xenobiotic-lipid conjugation. The latter research area, now in a state of infancy, is important toxicologically because the formation of xenobiotic-lipid conjugates might increase the persistence of a xenobiotic in the body (by its incorporation into a lipid storage form) or the xenobiotic-lipid conjugate itself might cause toxicity. The hypothesis will be tested that PFDA is more persistent in the rat than PFOA because it is esterified into acylglcerols (lipid storage form) while PFOA is almost entirely excluded from esterification. Lipophilic conjugates of each compound will be separated, identified and quantified. In perfused rat liver, metabolism of PFOA and PFDA and its effects on oxidation of medium and long-chain fatty acids will be studied. It will be ascertained whether effects of PFOA and PFDA on hepatic lipid metabolism result from depletion of free coenzyme A (CoA) or, more likely, formation of PFOA and PFDA-CoA thioesters as toxic lipophilic conjugates. In primary rat hepatocyte cultures, interrelationships between induction of fatty acyl-CoA oxidase and lauric acid hydroxylase, and inhibition of medium and long-chain fatty acid oxidation, will be examined. PFOA and PFDA will be evaluated in rats for hepatocarcinogenic potential. Until now, no peroxisome proliferator has been identified which does not cause hepatocellular carcinomas in rats and mice in long-term studies. Perfluorinated fatty acids might be the exception as recent findings suggest that PFOA is not hepatocarcinogenic. By evaluating if PFDA and PFOA act as initiators and/or promoters of rat hepatocarcinogenesis, the putative role of peroxisome proliferation in liver cancer might be better understood.

全氟脂肪酸，以全氟辛酸为代表全氟辛酸（PFOA）和全氟癸酸（PFDA）是一类新的过氧化物酶体增殖物。与其他类别（降血脂药物和邻苯二甲酸酯），它们产生显著的多效性反应在啮齿动物的肝脏中。没有关于代谢命运的信息， PFOA或PFDA，它们对肝脏脂肪酸氧化的影响，或它们干扰正常脂质代谢的机制。大鼠 PFDA比PFOA更具生物效力，但原因是未知这些药物的致癌潜力也是不知道。全氟脂肪酸具有潜在的重要性化学品的研究，因为他们（1）有广泛的商业用法，（2）是一类新的过氧化物酶体增殖剂，可能不具有致癌性，（3）可作为研究的探针正常的脂质代谢，和（4）可能是有用的原型，研究异生物质-脂质结合。后一个研究领域，现在处于婴儿期，在毒理学上是重要的，因为外源性脂质结合物的形成可能增加外源性物质在体内的持久性（通过将其掺入脂质储存形式）或外源性生物质-脂质缀合物本身可能会导致中毒。将检验PFDA是在大鼠体内比PFOA更持久，因为它被酯化成酰基甘油（脂质储存形式），而PFOA几乎完全是不包括酯化。每种的亲脂缀合物将对化合物进行分离、鉴定和定量。灌注大鼠肝脏，PFOA和PFDA代谢及其对氧化的影响中链和长链脂肪酸将被研究。将确定PFOA和PFDA对肝脏脂质的影响代谢是由于游离辅酶A（CoA）的消耗，或更多 PFOA和PFDA-CoA硫酯的形成可能是有毒的亲脂性缀合物。在原代大鼠肝细胞培养物中，脂肪酰辅酶A氧化酶的诱导与月桂酸羟化酶，以及中长链脂肪酸氧化，将被检查。 PFOA和PFDA将在在大鼠中评价肝癌的可能性。直到现在，没有过氧化物酶体增殖剂已被确定，长期研究中大鼠和小鼠的肝细胞癌。全氟脂肪酸可能是例外，研究结果表明，PFOA不是肝癌。通过评估PFDA和PFOA是否作为引发剂和/或促进剂，大鼠肝癌发生，过氧化物酶体的作用肝癌的扩散可能会更好地理解。