Mathematical Modeling of Serum 13C-Retinol in Captive Rhesus Monkeys Provides New Insights on Hypervitaminosis A
Mathematical Modeling of Serum 13C-Retinol in Captive Rhesus Monkeys Provides New Insights on Hypervitaminosis A
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DOI：
10.3945/jn.109.111922
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发表时间：
2009-10-01
影响因子：
4.2
通讯作者：
Tanumihardjo, Sherry A.
中科院分区：
文献类型：
--
作者：
Escaron, Anne L.;Green, Michael H.;Tanumihardjo, Sherry A.
维生素A过多症日益成为一个公共卫生问题，因此非侵入性定量方法值得探索。在这项研究中，我们应用C-13-视黄醇同位素稀释试验的非人灵长类动物模型与过量的肝脏储存。在基线血清化学后，给予恒河猴（Macaca mulatta; n = 16）3.5 μ mol C-13（2）-醋酸视黄酯。在基线、给药后5 h和2、4、7、14、21和28 d采血。在给药前7 d和给药后2 d（n = 4）以及给药后7、14和28 d（n = 4/次）采集肝活检组织。血清和肝脏分别用HPLC和GC-燃烧-同位素比MS分析视黄醇及其富集。将基于模型的房室分析应用于血清数据。50%的猴子乳酸脱氢酶升高。计算28 d时维生素A（VA）的总身体储备（TBR）。预测TBR（3.52 +/- 2.01 mmol VA）代表实测肝脏储存（4.56 +/- 1.38 mmol VA; P = 0.124）。预测的肝脏VA浓度（13.3 +/- 9.7 μ mol/g）与测量的肝脏VA浓度（16.4 +/- 5.3 μ mol/g）相似。动力学模型预测，27-52%的血管外VA是与血清中维生素A过多的猴子交换。该测试正确地诊断了所有猴子的维生素A过多症，即100%的灵敏度。稳定同位素技术对于VA状态的分类具有重要的公共卫生潜力，包括维生素过多症，因为除了侵入性肝活检外，没有其他技术可以正确识别过量的肝脏VA储存。J.营养139：2000-2006，2009.
Hypervitaminosis A is increasingly a public health concern, and thus noninvasive quantitative methods merit exploration. In this study, we applied the C-13-retinol isotope dilution test to a nonhuman primate model with excessive liver stores. After baseline serum chemistries, rhesus macaques (Macaca mulatta; n = 16) were administered 3.5 mu mol C-13(2)-retinyl acetate. Blood was drawn at baseline, 5 h, and 2, 4, 7, 14, 21, and 28 d following the dose. Liver biopsies were collected 7 d before and 2 d after dosing (n = 4) and at 7, 14, and 28 d (n = 4/time) after dosing. Serum and liver were analyzed by HPLC and GC-combustion-isotope ratio MS for retinol and its enrichment, respectively. Model-based compartmental analysis was applied to serum data. Lactate dehydrogenase was elevated in 50% of the monkeys. Total body reserves (TBR) of vitamin A (VA) were calculated at 28 d. Predicted TBR (3.52 +/- 2.01 mmol VA) represented measured liver stores (4.56 +/- 1.38 mmol VA; P = 0.124). Predicted liver VA concentrations (13.3 +/- 9.7 mu mol/g) were similar to measured liver VA concentrations (16.4 +/- 5.3 mu mol/g). The kinetic models predict that 27-52% of extravascular VA is exchanging with serum in hypervitaminotic A monkeys. The test correctly diagnosed hypervitaminosis A in all monkeys, i.e. 100% sensitivity. Stable isotope techniques have important public health potential for the classification of VA status, including hypervitaminosis, because no other technique besides invasive liver biopsies, correctly identifies excessive liver VA stores. J. Nutr. 139: 2000-2006, 2009.