Dietary RA

We have also studied the effects of RA on whole-body vitamin A metabolism (Lewis, 1987). All-trans-RA is an active metabolite of vitamin A that regulates numerous physiological processes in normal cells. Before the discovery of the molecular mechanisms of RA action, it was shown that dietary RA could partially substitute for vitamin A, influence hepatic vitamin A levels, and spare whole-body vitamin A stores (Lamb et al., 1974). In view of these observations, we were interested in the effects of chronic RA administration on vitamin A kinetics in rats with low vitamin A status. Using data collected in an in vivo kinetic study done at the same time as that on rats with low vitamin A status (Lewis et al., 1990), parallel models were developed for rats with low vitamin A status with or without RA supplementation (Cifelli et al., 2005). To develop models for individual organs, the "forcing function'' option in WinSAAM was applied (Wastney et al., 1999, pp. 123-126) (see earlier discussion). Once all organs were satisfactorily fit for each group, the forcing function was removed and the entire data set was modeled together, allowing for the determination of various kinetic parameters. The final model is shown in Fig. 9. Despite its apparent complexity, the model indicates that two compartments were needed to fit data for most of the organs examined in this study. That is, each organ could be characterized kinetically by a fast turning-over compartment that exchanges retinol with both plasma and the second, more slowly turning-over compartment in that organ. Therefore, despite differences in the physiological and molecular

FIGURE 9. Compartmental model for vitamin A metabolism in rats with low vitamin A status with or without supplementation with dietary RA. Compartments are shown as circles and sampled tissues are indicated within rectangles; movement between compartments is represented by arrows and quantified by fractional transfer coefficients [L(I,J)s or the fraction of compartment J's retinol transferred to compartment I per unit time]. U(1) represents input of newly absorbed dietary retinol, and the asterisk shows the site of introduction of the tracer (plasma). Irreversible loss from the system was modeled from carcass compartment 12 to a sink (compartment 20).

FIGURE 9. Compartmental model for vitamin A metabolism in rats with low vitamin A status with or without supplementation with dietary RA. Compartments are shown as circles and sampled tissues are indicated within rectangles; movement between compartments is represented by arrows and quantified by fractional transfer coefficients [L(I,J)s or the fraction of compartment J's retinol transferred to compartment I per unit time]. U(1) represents input of newly absorbed dietary retinol, and the asterisk shows the site of introduction of the tracer (plasma). Irreversible loss from the system was modeled from carcass compartment 12 to a sink (compartment 20).

processes involved in retinol metabolism in various organs, the compartmental structures for the different organs are kinetically alike.

The tracer response curves for the liver (Fig. 6), kidneys, small intestine, and lungs of RA-treated rats were visually different from the unsupplemen-ted rats as early as 2 h after administration of label. These differences were reflected in the model-predicted kinetic parameters. Specifically, the tissue residence times for vitamin A in the liver, kidneys, small intestine, and lungs were 14, 3.5, 5, and 75 times greater, respectively, in the RA-treated rats as compared to the unsupplemented ones. Similarly, the total traced mass of vitamin A in liver, kidneys, small intestine, and lungs was 11, 3, 5, and 31 times greater, respectively, in the RA-treated rats. The differences in the observed and model-predicted fractions of injected dose were a result of increased fractional input and decreased fractional output of vitamin A in the liver, kidneys, small intestine, and lungs of the RA-treated rats. For the other organs studied (eyes, testes, adrenals, and remaining carcass), there were no differences in vitamin A kinetics between the groups.

The differences in individual organ vitamin A kinetics were paralleled by differences in whole-body vitamin A kinetics in RA-supplemented versus untreated rats. For instance, the model-predicted vitamin A disposal rate was 20% lower, and the system fractional catabolic rate was 50% lower, in RA-treated rats. Together, the lower disposal and system catabolic rates contributed to a greater system residence time and total traced mass in the RA-treated rats, as evidenced by the differences in the tracer response curves for liver between the groups (Fig. 6). It is interesting that the liver tracer response curve for rats with low vitamin A status supplemented with RA was kinetically similar to the curve for rats with marginal vitamin A stores. These results suggest that retinol kinetics in liver are directly affected by hepatic vitamin A levels (Fig. 6). Overall, we concluded that vitamin A recycling, uptake, and mass were affected in a tissue-specific manner in rats with low vitamin A status during chronic RA administration. This resulted in retinol sparing and a positive vitamin A balance as was observed in earlier studies (Dowling and Wald, 1960; Lamb et al., 1974).

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