TOXICOLOGY OF PERFLUORINATED FATTY ACID-LIPID CONJUGATES

全氟化脂肪酸，以全氟辛酸为代表 全氟辛酸(PFOA)和全氟辛酸(PFDA)是一类新的 过氧化物酶增殖物。像其他类别一样(降血脂药物 和邻苯二甲酸酯)，它们能产生显著的多效性反应 在啮齿动物的肝脏里。目前还没有关于新陈代谢命运的信息 全氟辛酸或PFDA，它们对肝脏脂肪酸氧化的影响，或 它们扰乱正常脂肪代谢的机制。在大鼠身上 PFDA在生物学上比全氟辛酸更有效，但其原因是 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。 需要学习的化学品，因为它们(1)具有广泛的商业价值 用法，(2)是一类新的过氧化物酶增殖物，可能 不致癌，(3)可作为研究的探针 脂肪代谢正常，以及(4)可能是有用的原型 研究异种生物-脂质偶联。后一个研究领域， 现在处于婴儿期，在毒理学上很重要，因为 异种生物-脂质结合物的形成可能会增加 外来物在体内的持久性(通过将其合并到 脂存储形式)或异种生物-脂结合物本身 可能会导致中毒。这一假设将得到检验，即PFDA是 在大鼠体内比全氟辛酸更持久，因为它被酯化成 酰甘油(脂储存形式)，而全氟辛酸几乎完全 被排除在酯化之外的。每种化合物的亲脂结合物 化合物将被分离、鉴定和定量。在灌流中 全氟辛酸和PFDA在大鼠肝脏中的代谢及其对氧化的影响 将对中链和长链脂肪酸进行研究。会是 确定全氟辛酸和PFDA是否对肝脂有影响 新陈代谢是由于游离辅酶A(CoA)耗尽或更多 可能，全氟辛酸和PFDA-CoA硫代酯的形成是有毒的 亲脂性结合物。在原代培养的大鼠肝细胞中， 脂肪酰辅酶A氧化酶的诱导及其与酶活性的关系 月桂酸羟基酶及其对中长链的抑制 脂肪酸氧化，将进行检查。全氟辛酸和美国食品药品监督管理局将 在大鼠身上评估其诱发肝癌的可能性。到目前为止，没有 已发现不会引起 长期研究中的大鼠和小鼠的肝细胞癌。 全氟脂肪酸可能是最近的一个例外 研究结果表明，全氟辛酸不会致癌。通过 评估PFDA和全氟辛酸是否作为 大鼠肝细胞癌的发生、发展及其与过氧化物酶的关系 人们可能会更好地了解肝癌的增殖情况。

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.