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 (PFOA) 和全氟癸酸 (PFDA) 是一类新的过氧化物酶体增殖剂。与其他类一样（降血脂药和邻苯二甲酸酯）它们产生显着的多效性反应在啮齿动物肝脏中。没有关于代谢命运的信息 PFOA 或 PFDA，它们对肝脂肪酸氧化的影响，或它们扰乱正常脂质代谢的机制。在大鼠中 PFDA 比 PFOA 具有更强的生物效力，但原因是未知。这些药物的致癌潜力也不知道。全氟脂肪酸具有潜在的重要作用研究化学品是因为它们 (1) 具有广泛的商业价值用途，（2）是一类新的过氧化物酶体增殖剂，可能不会致癌，(3) 可以作为研究的探针正常的脂质代谢，并且（4）可能是有用的原型研究异生物质-脂质缀合。后一个研究领域，现在处于婴儿期，在毒理学上很重要，因为异生素-脂质缀合物的形成可能会增加异生素在体内的持久性（通过将其掺入脂质储存形式）或异生素-脂质缀合物本身可能会引起毒性。假设将被检验，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 几乎完全是排除酯化反应。每个的亲脂性缀合物化合物将被分离、鉴定和定量。灌注中大鼠肝脏、PFOA 和 PFDA 代谢及其对氧化的影响将研究中链和长链脂肪酸。这将是确定 PFOA 和 PFDA 对肝脂质是否有影响新陈代谢是由于游离辅酶 A (CoA) 或更多物质的消耗而导致的可能形成有毒的 PFOA 和 PFDA-CoA 硫酯亲脂性缀合物。在原代大鼠肝细胞培养中，脂肪酰辅酶A氧化酶的诱导与月桂酸羟化酶，以及中链和长链的抑制脂肪酸氧化，将被检查。 PFOA 和 PFDA 将在大鼠中评估其致癌潜力。到现在为止，没有已鉴定过氧化物酶体增殖物不会导致大鼠和小鼠肝细胞癌的长期研究。全氟脂肪酸可能是个例外，因为最近研究结果表明，PFOA 不会致癌。经过评估 PFDA 和 PFOA 是否充当发起者和/或促进者大鼠肝癌发生，过氧化物酶体的假定作用肝癌的增殖可能会得到更好的理解。