Quantitative analysis and chronic dosimetry of the aflatoxin B1 plasma albumin adduct Lys-AFB1 in rats by isotope dilution mass spectrometry
Quantitative analysis and chronic dosimetry of the aflatoxin B1 plasma albumin adduct Lys-AFB1 in rats by isotope dilution mass spectrometry
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DOI：
10.1021/tx050251r
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发表时间：
2006-01-01
影响因子：
4.1
通讯作者：
Groopman, JD
中科院分区：
文献类型：
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作者：
Scholl, PF;McCoy, L;Groopman, JD
黄曲霉毒素B-1（AFB（1））是亚洲和撒哈拉以南非洲地区肝癌发病的主要危险因素。反映接触情况的生物标志物将有助于疾病风险评估和保护性干预措施在这些人群中的效力。血浆白蛋白中的Lys-AFB（1）加合物是这种作用的候选生物标志物。虽然黄曲霉毒素白蛋白加合物在流行病学研究中最常使用酶联免疫吸附测定法进行测量，但最近出现了一种更特异、灵敏度高10倍的Lys-AFB同位素稀释质谱测定法（1）。在此，使用该测定法探索了长期给予低于先前研究剂量的AFB（1）的剂量学。AFB（1）以50 μ g/kg体重至55 μ g/kg体重的8个剂量水平连续给药9天。血浆样品经酶消化并通过固相萃取处理。Lys-AFB（1）通过HPLC分离，并通过选择性反应监测进行检测。剂量-反应关系为线性二次关系，在较高剂量下表现出向上的曲率。加合物产量[（pg Lys-AFB（1）/mg白蛋白）/（μ g AFB（1）/kg体重）]在0.05和55 μ g AFB（1）/kg体重组之间随剂量非线性增加6倍，在最高剂量组中开始饱和，其中加合物产量约为2%。对暴露时间的不完全了解和潜在生物学的复杂性，使人先前暴露于AFB（1）的精确测定变得混乱;然而，在长期服用AFB（1）的大鼠中观察到的AFB（1）的剂量测定从概念上表明，如果AFB（1）剂量的恒定分数，大约2%，假定转化为Lys-AFB（1），与剂量无关。
Aflatoxin B-1 (AFB(1)) is a major risk factor in the pathogenesis of liver cancer in Asia and sub-Saharan Africa. Biomarkers reflecting exposure will facilitate disease risk assessment and the efficacy of protective interventions in these populations. The Lys-AFB(1) adduct in plasma albumin is a candidate biomarker for this role. Although aflatoxin albumin adducts are most frequently measured in epidemiological studies using an enzyme-linked immunosorbent assay, a more specific and 10-fold more sensitive isotopic dilution mass spectrometric assay for Lys-AFB(1) has recently become available. Here, the dosimetry of chronically administered AFB(1) at lower doses than have been previously studied was explored using this assay. AFB(1) was administered to rats for nine consecutive days at eight dose levels ranging from 50 pg to 55 mu g/kg body wt. Plasma samples were enzymatically digested and processed by solid phase extraction. Lys-AFB(1) was isolated by HPLC and detected via selected reaction monitoring. The dose-response relationship was linear-quadratic exhibiting upward curvature at higher doses. The adduct yield [(pg Lys-AFB(1)/mg albumin)/(mu g AFB(1)/kg body wt)] increased nonlinearly with the dose by 6-fold between the 0.05 and 55 mu g AFB(1)/kg body wt groups and exhibited the onset of saturation in the highest dose group where the adduct yield was approximately 2%. Incomplete knowledge of the timing of exposure and the complexity of the underlying biology confound the precise determination of prior AFB(1) exposures in humans; however, the dosimetry of AFB(1) observed in chronically dosed rats conceptually suggests that measurements in humans may underestimate exposure if a constant fraction of the AFB(1) dose, approximately 2%, is assumed to be converted to Lys-AFB(1) without regard to the dose.