Systemic uptake, albumin and hemoglobin binding of [14C]2,3-butanedione administered by intratracheal instillation in male Harlan Sprague Dawley rats and oropharyngeal aspiration in male B6C3F1/N mice
Systemic uptake, albumin and hemoglobin binding of [14C]2,3-butanedione administered by intratracheal instillation in male Harlan Sprague Dawley rats and oropharyngeal aspiration in male B6C3F1/N mice
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DOI：
10.1016/j.cbi.2014.12.029
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发表时间：
2015-02-05
影响因子：
5.1
通讯作者：
Waidyanatha, Suramya
中科院分区：
文献类型：
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作者：
Fennell, Timothy R.;Morgan, Daniel L.;Waidyanatha, Suramya
2，3-丁二酮（BD）是人造黄油香料中的一种反应性二酮，被认为会导致微波爆米花制造工人的闭塞性细支气管炎。闭塞性细支气管炎通常在发生不可逆损伤后才被诊断;因此需要早期暴露的生物标志物。尚未评价吸入暴露对BD的潜在全身吸收。本研究旨在评价BD的全身暴露量以及与血红蛋白和白蛋白的结合。雄性哈兰Sprague道利大鼠（100 mg/kg，气管内滴注）和B6 C3 F（1/N）小鼠（157 mg/kg，口咽抽吸）给予[C-14]BD。给药后24小时采集血液和血浆，并分析C-14含量。24 h时，大鼠血液中的给药剂量为0.88 +/- 0.07%，大鼠血浆中为0.66 +/- 0.06%，小鼠血液中为0.38 +/- 0.13%，小鼠血浆中为0.17 +/- 0.05%。大鼠中的白蛋白结合为269 +/- 24.2 ng当量/ mg，占血浆放射性的38%。在小鼠中，结合为85.0 +/- 22.3 ng当量/ml。mg白蛋白，占血浆放射性的51%。与大鼠血红蛋白的结合为38.2 +/- 17.6 ng当量/ mg，对珠蛋白的反应为29.1 +/- 3.96 ng当量/ml。mg.在小鼠中，与血红蛋白的结合为16.2 +/- 9.0 ng当量/ml。mg.通过质谱法研究血红蛋白和白蛋白上的加合位点。在大鼠珠蛋白中，在体外和体内的β链的R-30和R-104处检测到精氨酸加合物。在大鼠白蛋白中，在体外检测到R-219/221、R-360和R-368的加合物，在体内检测到各种精氨酸残基的加合物。该研究表明，BD进入体循环并与血红蛋白和白蛋白上的精氨酸反应。这些结果表明，血红蛋白和白蛋白加合物可能是有用的生物标志物的BD暴露在人类。(C)2014爱思唯尔爱尔兰有限公司版权所有。
2,3-Butanedione (BD) is a reactive diketone in artificial butter flavors that is thought to cause bronchiolitis obliterans in workers in microwave popcorn manufacturing. Bronchiolitis obliterans is generally not diagnosed until irreversible damage has occurred; therefore a biomarker of early exposure is needed. The potential systemic uptake of BD from inhalation exposure has not been evaluated. The objective here was to evaluate the systemic exposure of BD and binding to hemoglobin and albumin. [C-14]BD was administered to male Harlan Sprague Dawley rats (100 mg/kg, intratracheal instillation) and B6C3F(1/N) mice (157 mg/kg, oropharyngeal aspiration). Blood and plasma was collected 24 h after administration and analyzed for C-14 content. At 24 h, 0.88 +/- 0.07% of the administered dose was in rat blood, 0.66 +/- 0.06% in rat plasma, 0.38 +/- 0.13% in mouse blood and 0.17 +/- 0.05% in mouse plasma. Albumin binding in rats was 269 +/- 24.2 ng equiv./mg, which accounts for 38% of the radioactivity in plasma. In mice, binding was 85.0 +/- 22.3 ng equiv./mg albumin, which accounts for 51% of the radioactivity in plasma. The binding to hemoglobin in rats was 38.2 +/- 17.6 ng equiv./mg, and to globin was 29.1 +/- 3.96 ng equiv./mg. In mice, the binding to hemoglobin was 16.2 +/- 9.0 ng equiv./mg. The site(s) of adduction on hemoglobin and albumin was investigated by mass spectrometry. In rat globin, arginine adducts were detected at R-30 and R-104 of the beta chain in vitro and in vivo. In rat albumin, adducts were detected in vitro on R-219/221, R-360, and R-368, and in vivo on a variety of arginine residues. This study demonstrated that BD enters the systemic circulation and reacts with arginine on hemoglobin and albumin. These results indicate that hemoglobin and albumin adducts may be useful as biomarkers of BD exposure in humans. (C) 2014 Elsevier Ireland Ltd. All rights reserved.