Tissue distribution, metabolism, and elimination of perfluorooctanoic acid in male and female rats.
Tissue distribution, metabolism, and elimination of perfluorooctanoic acid in male and female rats.
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DOI：
10.1002/jbt.2570060202
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发表时间：
1991-06
期刊：
影响因子：
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通讯作者：
John P. Vanden Heuvel;Benedict I. Kuslikis;M. J. Rafelghem;R. E. Peterson
中科院分区：
文献类型：
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作者：
John P. Vanden Heuvel;Benedict I. Kuslikis;M. J. Rafelghem;R. E. Peterson
在雄性和雌性大鼠中，在单次腹腔注射剂量（9.4μmol/kg，4mg/kg）后28天检查[1-14C]全氟辛酸（PFOA）的消除、组织分布和代谢。观察到 PFOA 衍生的 14C 尿液消除存在性别差异。雌性大鼠在尿液中迅速消除了 PFOA 衍生的放射性，91% 的剂量在前 24 小时内被排出。同一时期，雄性大鼠尿液中仅排出了 6% 的 14C。尿消除中性别相关的差异导致男性（t1/2 = 15 天）和女性（t1/2 小于 1 天）中 PFOA 的全身消除半衰期 (t1/2) 存在差异。对组织中PFOA源14C的分析表明，雄性大鼠的肝脏和血浆以及雌性大鼠的肝脏、血浆和肾脏是主要分布的组织。使用原位非循环肝脏灌注技术进一步检查了男性肝脏中相对较高浓度的 PFOA。研究表明，11% 的 PFOA 一次性被肝脏提取。在结扎肾蒂以减轻 PFOA 尿液排泄的性别差异的大鼠中，检查了肝脏将 PFOA 消除到胆汁中的能力。在腹腔注射 PFOA 后的 6 小时内，胆汁排泄没有明显差异，男性和女性通过此途径消除的 PFOA 剂量均不到 1%。我们假设 PFOA 持久性的性别差异是由于雄性大鼠中含有 PFOA 的脂质（即含有 PFOA 的单酰基甘油、二酰基甘油或三酰基甘油、胆固醇酯、甲酯或磷脂）更快形成。此外，女性尿液中 PFOA 消除量的增加可能是由于 PFOA-葡萄糖醛酸或硫酸酯的代谢增加所致。然而，没有证据表明 PFOA 结合形成持久性混合脂质，也没有在尿液或胆汁中检测到 PFOA 的极性代谢物。此外，雄性和雌性大鼠在 PFOA 治疗前后每日尿液中氟化物的排泄量相似，表明母体化合物并未脱氟。因此，雌性大鼠体内 PFOA 更快消除并不是由于 PFOA 代谢物的形成。
The elimination, tissue distribution, and metabolism of [1-14C]perfluorooctanoic acid (PFOA) was examined in male and female rats for 28 days after a single ip dose (9.4 mumol/kg, 4 mg/kg). A sex difference in urinary elimination of PFOA-derived 14C was observed. Female rats eliminated PFOA-derived radioactivity rapidly in the urine with 91% of the dose being excreted in the first 24 hr. In the same period, male rats eliminated only 6% of the administered 14C in the urine. The sex-related difference in urinary elimination resulted in the observed difference in the whole-body elimination half-life (t1/2) of PFOA in males (t1/2 = 15 days) and females (t1/2 less than 1 day). Analysis of PFOA-derived 14C in tissues showed that the liver and plasma of male rats and the liver, plasma, and kidney of female rats were the primary tissues of distribution. The relatively high concentration of PFOA in the male liver was further examined using an in situ nonrecirculating liver perfusion technique. It was shown that 11% of the PFOA infused was extracted by the liver in a single pass. The ability of the liver to eliminate PFOA into bile was examined in rats whose renal pedicles were ligated to alleviate sex differences in the urinary excretion of PFOA. In a 6-hr period following IP administration of PFOA, there was no apparent difference in biliary excretion, where both males and females eliminated less than 1% of the PFOA dose via this route. We hypothesized that the sex difference in the persistence of PFOA was due to a more rapid formation of a PFOA-containing lipid (i.e., a PFOA-containing mono-, di-, or triacylglycerol, cholesteryl ester, methyl ester, or phospholipid) in the male rat. Also, the increased urinary elimination of PFOA in females may have been due to increased metabolism to a PFOA-glucuronide or sulfate ester. However, no evidence that PFOA is conjugated to form a persistent hybrid lipid was obtained, nor were polar metabolites of PFOA in urine or bile detected. In addition, daily urinary excretion of fluoride in male and female rats before or after PFOA treatment were similar, suggesting that the parent compound is not defluorinated. Thus, the more rapid elimination of PFOA from female rats is not due to formation of a PFOA metabolite.