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Methodology and Mathematical Modeling

Kinetic Analysis Shows that Vitamin A Disposal Rate in Humans Is Positively Correlated with Vitamin A Stores^1,2

³ Department of Nutritional Sciences, Pennsylvania State University, University Park, PA 16802; ⁴ National Institute for Nutrition and Food Safety, Chinese Centre for Disease Control and Prevention, Beijing, China 100050; ⁵ Institute of Medical Nutrition, Qingdao, China 266021; and ⁶ USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111

^* To whom correspondence should be addressed. E-mail: mhg{at}psu.edu.

	ABSTRACT

TOP ABSTRACT Introduction Subjects and Methods Results Discussion LITERATURE CITED

 
Vitamin A (VA) kinetics, storage, and disposal rate were determined in well-nourished Chinese and U.S. adults using model-based compartmental analysis. [²H₈]Retinyl acetate (8.9 µmol) was orally administered to U.S. (n = 12; 59 ± 9 y; mean ± SD) and Chinese adults (n = 14; 54 ± 4 y) and serum tracer and VA concentrations were measured from 3 h to 56 d. Using the Windows version of the Simulation, Analysis and Modeling software, we determined that the average time from dosing until appearance of labeled retinol in serum was greater in U.S. subjects (40.6 ± 8.47 h) than in Chinese subjects (32.2 ± 5.84 h; P < 0.01). Model-predicted total traced mass (898 ± 637 vs. 237 ± 109 µmol), disposal rate (14.7 ± 5.87 vs. 5.58 ± 2.04 µmol/d), and system residence time (58.9 ± 28.7 vs. 42.9 ± 14.6 d) were greater in U.S. than in Chinese subjects (P < 0.05). The model-predicted VA mass and VA mass estimated by deuterated retinol dilution at 3 and 24 d did not differ. VA disposal rate was positively correlated with VA traced mass in Chinese (R² = 0.556), U.S. (R² = 0.579), and all subjects (R² = 0.808). Additionally, VA disposal rate was significantly correlated with serum retinol pool size (R² = 0.227) and retinol concentration (R² = 0.330) in all subjects. Our results support the hypothesis that VA stores are the principle determinant of VA disposal rate in healthy, well-nourished adults.

	Introduction

TOP ABSTRACT Introduction Subjects and Methods Results Discussion LITERATURE CITED

Because one of the determinants of the dietary requirements for VA is VA utilization, it is important to determine the factors that influence VA turnover and disposal. Previous work in humans and rats has demonstrated that different nutritional (5,6), environmental (7,8), and disease conditions (9–12) alter VA homeostasis. Studies in rats have established that, as VA intake and stores increased, there was a parallel increase in VA utilization (13). Similarly, Hicks et al. (14) reported that biliary VA disposal was higher in rats with high hepatic stores of the vitamin. When VA turnover was quantified in rats with low, marginal, and high liver VA stores by Green et al. (15), the results showed that VA disposal and turnover were different among the groups, suggesting that VA kinetics responds to changes in dietary VA intake. Finally, Kelley and Green (16) investigated the factors that influence VA disposal in VA-adequate rats under conditions of low VA intake. The authors showed that, if liver stores were adequate, VA disposal was not decreased to compensate for low VA intake as long as plasma retinol concentration was normal, suggesting that VA disposal is also influenced by plasma retinol concentrations.

Although these studies have delineated some of the underlying mechanisms governing VA turnover in rats, only a few studies (17–19) have examined VA kinetics in humans. For instance, Sauberlich et al. (17) showed that VA disposal is related to total body stores, noting that both plasma VA concentration and utilization rate decreased during depletion to conserve VA when intake was low. More recently, von Reinersdorff et al. (18,19) utilized a stable isotope method to describe and quantify the absorption and metabolism of retinyl palmitate in men. A compartmental model developed to fit data for 1 of the subjects predicted that retinol recycling through plasma was substantially higher than the VA disposal rate (19), as has also been shown in rats (20).

In view of the limited data on VA turnover and disposal in humans, we developed a compartmental model that describes and quantifies the kinetics of VA absorption and metabolism following the oral administration of a stable isotope of VA to well-nourished Chinese (21) and American adults (22). In addition to the quantitative and descriptive information obtained from the models, our results confirm the hypothesis that, in individuals with normal VA status, VA disposal rate is influenced more by VA stores than by serum retinol levels.

	Subjects and Methods

TOP ABSTRACT Introduction Subjects and Methods Results Discussion LITERATURE CITED

 
    Labeled retinyl acetate. [²H₈]RAc (10, 14, 19, 19, 19, 20, 20, 20-²H₈-retinyl acetate) was purchased from Cambridge Isotope Laboratories and dissolved in corn oil (21,22). The chemical purity of the [²H₈]RAc was >98%. All procedures involving VA were carried out under red or dim light.

    Subjects. As part of 2 larger studies that examined the conversion of β-carotene to retinol in Chinese (21) and U.S. adults (22), data from a subset of participants (n = 14 Chinese, 12 US) were analyzed using model-based compartmental analysis (see below). All volunteers had the following characteristics: 40–71 y old; nonsmokers; had not taken a VA or β-carotene supplement within the past month; had body weights within 20% of the standard for their height and a BMI 30 kg/m²; and had no acute or chronic disease signs or symptoms (21,22). Informed written consent was obtained from all volunteers under the guidelines established by both the Ethical Review Committee of the Institute of Nutrition and Food Hygiene, Chinese Academy of Preventive Medicine and the Human Investigation Review Committee of Tufts University, Tufts-New England Medical Center for the Chinese participants and from the Tufts Review Committee for the American subjects.

    Study design and kinetic studies. The studies were conducted as described previously (21,22). Briefly, during the 2 wk prior to entering the experiment, participants were instructed by a dietitian to avoid vitamin supplements or foods containing large amounts of VA or β-carotene. Following the 2-wk introductory period, participants were housed in a metabolic research unit for a 10-d resident stay. After this, each participant was free-living from d 11 to 56; subjects were instructed not to consume vitamin supplements or foods containing large amounts of VA or β-carotene and dietitians followed up with each participant to ensure compliance.

On d 4 of the resident stay, participants swallowed a capsule containing 3 mg [²H₈]RAc (8.9 µmol) in 170 mg corn oil and consumed a formulated liquid breakfast containing 25% energy from fat (21,22). Serum samples were collected by venipuncture at baseline and 3, 5, 7, 9, 11, and 13 h following administration of [²H₈]RAc. In addition, fasting serum samples were collected daily for the following 6 d and then weekly for 7 wk. Aliquots of serum were stored at –70°C for subsequent analysis.

    Analytical procedures. Aliquots of serum (100 µL) were extracted in 3 mL of chloroform:methanol (2:1, v:v) as described earlier (22). Samples were mixed by vortexing, centrifuged at 800 x g for 10 min at 4°C and the chloroform layer was collected. The remaining aqueous phase was reextracted with 2 mL of hexane, which was combined with the chloroform layer. The organic phase was dried to completeness under nitrogen gas using an N-EVAP (Organomation Associates). The residue was dissolved in 100 µL of ethanol and retinoid masses were quantified by reverse-phase HPLC (22). The percent enrichment of labeled retinol derived from RAc was determined using GC-electron capture negative chemical ionization MS as previously described (22).

    Kinetic analysis and parameters. Data on fraction of the administered dose remaining in serum at each time were calculated as serum tracer concentration divided by the dose divided by the estimated serum volume. Serum volume was calculated as body weight (g) x 0.038 mL serum/g body weight (23). Then, using the Windows version of the Simulation, Analysis and Modeling computer program (WinSAAM) (24), we employed model-based compartmental analysis (25) to characterize whole-body VA kinetics for each individual as viewed from the plasma space. In this form of compartmental analysis, processes with similar kinetics are lumped in the same compartment. To determine the simplest model that would adequately fit the data for serum, model complexity was increased only when it resulted in a significant improvement in the weighted sums of squares as determined by an F-statistic (26). Once a satisfactory fit for each individual was obtained, weighted nonlinear regression analysis (fractional SD = 0.05) using WinSAAM was applied to obtain the final estimates of the fractional transfer coefficients [L(I,J); see below].

The following kinetic parameters were determined for each individual; see Green and Green (25) for more details. The L(I,J) (d^–1) are defined as the portion of VA in compartment J that is transferred to compartment I each day. Mean transit time [t(I); d] is defined as the average length of time that a molecule of VA that reaches compartment I remains in compartment I before it leaves that compartment reversibly or irreversibly. The average time for a molecule of VA to appear in the blood after ingestion of the oral dose was calculated by summing the transit times in each compartment that preceded the appearance of labeled retinol in serum. Serum VA pool sizes (µmol) were estimated from each individual's average serum VA concentration during the study and their estimated serum volume. Then, serum VA pool sizes were used in a steady-state solution in WinSAAM to estimate VA pool sizes or traced mass [M(I); µmol] and residence times [T(I,J); d; the average of the distribution of times that a molecule of retinol spends in compartment I before leaving that compartment irreversibly after entering the system via compartment J]. Because kinetic parameters were calculated assuming a steady state and given the relatively short duration of the study, VA input rate was set equal to the disposal rate.

    Determination of total-body VA using isotope dilution. Serum tracer ([²H₈]retinol) and tracee (retinol) were used to estimate total-body VA using the deuterated retinol dilution (DRD) technique (27). Briefly, total-body VA was calculated at 24 d after tracer administration using the equation:

where F is the fraction of dose absorbed and retained (estimated to be 0.5), S is the ratio of the specific activity of retinol in serum to that in liver (estimated to be 0.65), a is the correction for loss of tracer via catabolism (a = e^–kt, where k = 140 d), and H:D-1 is the measured tracee:tracer ratio corrected for the contribution of the mass of tracer retinol to total-body VA (27,28). We applied the DRD equation using data from d 24, because it has been estimated that it takes 20 d for orally administered labeled VA to mix with endogenous body pools (17,29,30). In addition, to determine whether total-body VA stores could be estimated at an earlier time, we modified the DRD equation by using d 3 tracee and tracer data to calculate both a ratio of specific activity of retinol in serum to that in liver (a) and a H:D ratio. We also estimated the fraction of dose absorbed and retained (F) to be 0.75 as opposed to 0.5 (31). Using these values in the above equation, total-body VA was calculated at 3 d after tracer administration.

    Statistics. All results are expressed as means ± SD. When appropriate, data were log-transformed to meet normality assumptions prior to statistical analysis. Kinetic data were compared statistically using a Student's unpaired t test in Microsoft Excel (2001 version); P < 0.05 was considered significant. Simple regression was performed using SuperANOVA (Abacus Concepts) on individual data, with P < 0.05 considered significant.

	Results

TOP ABSTRACT Introduction Subjects and Methods Results Discussion LITERATURE CITED

 
    Subject characteristics. The characteristics of the subjects and their baseline serum retinol concentrations are presented in Table 1. There were no significant differences between the Chinese and U.S. subjects in age, body weight, or BMI. Similarly, there were no differences in these characteristics when adjusted for gender (data not shown). Baseline serum retinol concentrations were normal in both groups, but concentrations were significantly higher in the U.S. adults (Table 1).

View larger version (9K): [in this window] [in a new window]   FIGURE 1  Mean observed (symbols) and model-predicted (lines) fraction of ingested dose in serum for a representative Chinese and U.S. subject vs. time (d) after administration of [2H8]RAc (8.9 µmol) in corn oil.

View larger version (7K): [in this window] [in a new window]   FIGURE 2  Proposed multicompartmental model for VA metabolism in Chinese and U.S. subjects. Compartments are represented as circles and interconnectivities between compartments correspond to L(I,J) (the fraction of retinol in compartment J that is transferred to compartment I each day; Table 2); compartment 3 is a delay element. Compartments 1–4 (including component 3) represent the physiological processes of VA digestion and absorption, chylomicron production and metabolism, liver uptake of chylomicron remnants, and hepatic processing of retinol. Compartment 5 represents serum retinol bound to RBP; this retinol exchanges with VA in 1 extravascular pool (compartment 6). The asterisk represents the site of input of [2H8]RAc and is also the site of input for dietary VA.

Compartmental modeling also predicted differences between groups in the VA disposal rate and the days of VA stores. The estimated average VA disposal rate (Table 3) for the U.S. group was 163% greater than that for the Chinese group. Based on differences in the model-predicted L(I,J) (Table 2), compartment masses (Table 3), and disposal rates (Table 3), we estimate that the U.S. adults had 37% more days of VA stores than the Chinese adults (Table 3).

To determine whether serum retinol pool size [M(5)], serum retinol concentration, and/or the model-predicted traced mass in the slow turning-over compartment [M(6)] affect VA utilization, the model-predicted VA disposal rates were compared with these variables using linear regression analysis. In both the Chinese and U.S. participants, VA disposal rate was significantly correlated with the traced mass in compartment 6 (the extravascular compartment), with the disposal rate increasing linearly with increasing VA stores (Fig. 3A,B). In addition, VA disposal rate was correlated with serum retinol concentration in the Chinese participants (R² = 0.336; P < 0.05; data not shown) but not with serum retinol pool size; VA disposal rate was not correlated with either serum retinol concentration or serum retinol pool in the U.S. group (data not shown). The strongest correlations were observed when individuals in both groups were combined (Chinese and US, n = 26). In all individuals, VA disposal rate was directly correlated with VA mass in the extravascular compartment (Fig. 4A), with serum retinol concentration (Fig. 4B), and with the serum retinol pool size (Fig. 4C). Additionally, serum retinol concentration was correlated with VA mass in the extravascular compartment (R² = 0.231; P < 0.05; data not shown).

View larger version (11K): [in this window] [in a new window]   FIGURE 3  Regression analysis of VA disposal rate (µmol/d) vs. compartment 6 traced mass (µmol) for Chinese (A; n = 14) and U.S. subjects (B; n = 12). Data were log-transformed prior to statistical analysis.

View larger version (9K): [in this window] [in a new window]   FIGURE 4  Regression analysis of VA disposal rate (µmol/d) vs. compartment 6 traced mass (A; µmol), serum retinol concentration (B; µmol/L), and compartment 5, or the serum retinol pool (C; µmol) in all subjects (n = 26). Data were log-transformed prior to statistical analysis.

View larger version (13K): [in this window] [in a new window]   FIGURE 5  Comparison of estimated total-body VA pool size estimated by the DRD technique at 3 or 24 d after oral administration of [2H8]RAc and from compartmental modeling for Chinese (white bar; n = 14) and U.S. subjects (black bar; n = 12). Bars are means + SD. Data were log-transformed prior to statistical analysis.

	Discussion

TOP ABSTRACT Introduction Subjects and Methods Results Discussion LITERATURE CITED

Using WinSAAM, we developed a 6-compartment model (Fig. 2) that describes the digestion, absorption, hepatic processing, and turnover of VA in Chinese and U.S. subjects. The compartmental model is similar to that presented previously for 1 human subject (28) and to a model recently developed for rats (34). In all cases, several compartments were required to describe the complex processes of VA digestion, absorption, and initial hepatic processing. In the model developed to fit rat data (34), 2 extravascular compartments, one a faster turning-over pool and the other more slowly turning-over, were required to fit serum tracer data, whereas in the human subjects studied here, 1 extravascular compartment was adequate to fit the data (Fig. 2). We speculate that this difference may be the result of the timing of blood sampling and the larger VA pool in humans, which resulted in "lumping" of the more rapidly turning-over VA with the more slowly turning-over pool. It is likely that a 2nd, more rapidly turning-over compartment would be required to fit data from humans with low to marginal VA stores.

Our model predicted differences in whole-body VA kinetics between the Chinese and U.S. subjects. Specifically, the mean model-predicted VA disposal rate, total traced mass, and VA T(I,J) in the slow turning-over compartment (compartment 6, Fig. 2) were significantly greater in the U.S. subjects (Table 3). Previous studies have demonstrated that serum retinol is the main determinant of VA disposal rate in rats with low to moderate VA intake (16), whereas VA status affected disposal rate in rats with higher liver stores (15). Our results appear to support those observed in rats with high liver VA stores (15) by showing that the model-predicted VA disposal rate was strongly correlated to VA total traced mass in Chinese (Fig. 3A), U.S. (Fig. 3B), and all subjects (Fig. 4A). Moreover, when we compared VA disposal rate to serum retinol concentrations in all subjects, we observed that retinol concentrations were correlated with VA disposal rate (Fig. 4B,C), indicating that serum retinol also contributes to whole-body VA disposal as previously reported (16).

In this study, both the Chinese and U.S. subjects were VA adequate. However, serum retinol concentrations were significantly higher in the U.S. adults than in Chinese adults. Based on these results, we hypothesize that, as VA stores increase, there is a parallel increase in serum VA concentrations, which results in increased VA disposal rate as observed in rat models (15,16). In contrast, as VA stores decrease over time, such as during VA deficiency, there will be a decrease in serum retinol concentrations that will result in decreased VA disposal rate to conserve VA. This hypothesis is supported by the findings of Sauberlich et al. (17), who showed that both plasma retinol concentrations and disposal decreased over time during VA depletion. Thus, differences in VA nutriture will lead to changes in VA kinetics that will alter VA disposal rate to either conserve VA (VA deficiency) or prevent excessive accumulation of VA (VA sufficiency) even when VA levels are adequate.

With regard to VA stores, previous work has demonstrated that the liver is the primary storage site for VA in rats and humans when VA intake is normal (35–37). It was therefore of interest to compare our model-predicted VA total traced masses to liver VA levels measured by biopsy in an older study (27). To make this comparison, we assumed that the model-predicted total traced mass in compartment 6 was equivalent to liver VA; we calculated liver VA concentration by assuming that the liver comprises 2.4% of total body weight (27). Using these assumptions, VA nutriture for both Chinese and U.S. subjects was adequate (>0.07 µmol/g) (38) and compared favorably to hepatic VA concentrations that had been measured previously (27). Moreover, our model-predicted VA stores are similar to the values determined by isotope dilution (Fig. 5; 27,28). These results suggest that model-based compartmental analysis could be a useful tool to estimate whole-body VA stores in individuals. Advantages of this method are that, in addition to estimating whole-body VA mass as opposed to only hepatic levels, other useful information (such as estimates of VA intake, retinol recycling, T(I,J), utilization rate, and distribution) is obtained. Although the technique requires only a low dose of stable isotope-labeled retinol, studies need to be carried out for a long period of time (50 d) and numerous blood samples are required.

When the DRD equation (27,28) was used here to estimate liver VA stores, data did not differ from 3 d and 24 d after dose administration (Fig. 5). Our results appear to support those in elderly Guatemalan men and women (30) by showing that liver VA stores can be estimated 3 d after tracer administration, thus increasing the efficacy of the DRD technique. Future studies should be conducted to validate and expand this finding so that a 3-d DRD equation can be developed to calculate an individual's VA stores.

In conclusion, a variety of techniques have been employed to attempt to determine the effect of dietary VA and VA status on the turnover and disposal of VA so that dietary requirements may be accurately estimated. Because the recommended daily allowances are set to meet the requirements for nearly all healthy individuals in a given age and gender group, this study was conducted to better understand VA kinetics in 2 groups of well-nourished individuals (Chinese vs. Americans). To our knowledge, this is the first study to use model-based compartmental analysis to examine whole-body VA kinetics for the purpose of determining the effect of VA stores on VA turnover and disposal rate in humans. The results of our work demonstrate that VA disposal rate is strongly associated with VA stores, suggesting that VA stores are a major determinant of VA disposal rate in well-nourished humans. Furthermore, we show that both model-based compartmental analysis and a modified DRD equation using 3-d data provide a good quantitative estimate of VA pool size in humans. Additional studies should be conducted to determine VA disposal in culturally diverse groups of humans across a range of VA nutriture and age.

	FOOTNOTES

 
¹ Supported in part by grants from the Chinese National Natural Science Foundation (no. 30271121 to Z. W.) and the USDA (no. 58-1950-7-707 to G. T.) (for experimental studies); modeling and manuscript preparation were supported by funds from Penn State's College of Health and Human Development.

² Author disclosures: C. J. Cifelli, J. B. Green, Z. Wang, S. Yin, R. M. Russell, G. Tang, and M. H. Green, no conflicts of interest.

⁷ Abbreviations used: DRD, deuterated retinol dilution; L(I,J), fractional transfer coefficient; M(I), mass in compartment I; RAc, retinyl acetate; RBP, retinol-binding protein; T(I,J), residence time; VA, vitamin A; WinSAAM, Windows version of the Simulation, Analysis and Modeling software.

Manuscript received 28 January 2008. Initial review completed 13 February 2008. Revision accepted 28 February 2008.

	LITERATURE CITED

TOP ABSTRACT Introduction Subjects and Methods Results Discussion LITERATURE CITED

 

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