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Methodology and Mathematical Modeling

Mathematical Modeling of Serum ¹³C-Retinol in Captive Rhesus Monkeys Provides New Insights on Hypervitaminosis A^1–3,

⁴ Interdepartmental Graduate Program in Nutritional Sciences, University of Wisconsin, Madison, WI 53706; ⁵ Department of Nutritional Sciences, Pennsylvania State University, University Park, PA 16802; and ⁶ Department of Agronomy and Soils, Auburn University, Auburn, AL 36849

Hypervitaminosis A is increasingly a public health concern, and thus noninvasive quantitative methods merit exploration. In this study, we applied the ¹³C-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 µmol ¹³C₂-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 µmol/g) were similar to measured liver VA concentrations (16.4 ± 5.3 µmol/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.

^* To whom correspondence should be addressed. E-mail: sherry{at}nutrisci.wisc.edu.

Manuscript received 22 June 2009. Initial review completed 20 July 2009. Revision accepted 11 August 2009.

Published online 26 August 2009.